Substituted phthalazinones as rock inhibitors

ABSTRACT

The present invention provides compounds of Formula (I): 
                         
or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.

FIELD OF THE INVENTION

The present invention relates generally to novel phthalazinone andisoquinolinone compounds, and their analogues thereof, which areinhibitors of Rho kinases, compositions containing them, and methods ofusing them, for example, for the treatment or prophylaxis of disordersassociated with aberrant Rho kinase activity.

BACKGROUND OF THE INVENTION

Rho-Kinase (ROCK) is a member of the serine-threonine protein kinasefamily. ROCK exists in two isoforms, ROCK1 and ROCK2 (T. Ishizaki etal., EMBO J., 1996, 15, 1885-1893). ROCK has been identified as aneffector molecule of RhoA, a small GTP-binding protein (G protein) thatplays a key role in multiple cellular signaling pathways. ROCK and RhoAare ubiquitously expressed across tissues. The RhoA/ROCK signalingpathway is involved in a number of cellular functions, such as actinorganization, cell adhesion, cell migration, and cytokinesis (K. Rientoand A. J. Ridley, Nat Rev Mol Cell Biol, 2003, 4, 446-56). It is alsodirectly involved in regulating smooth muscle contraction (A. P. Somlyo,Nature, 1997, 389, 908-911). Upon activation of its receptor, RhoA isactivated, and, in turn, it activates ROCK. Activated ROCKphosphorylates the myosin-binding subunit of myosin light chainphosphatase, which inhibits activity of the phosphatase and leads tocontraction. Contraction of the smooth muscle in the vasculatureincreases blood pressure, leading to hypertension.

There is considerable evidence in the literature that the Rho A/ROCKsignaling pathway plays an important role in signal transductioninitiated by several vasoactive factors, for example angiotensin II (T.Yamakawa et al., Hypertension, 2000, 35, 313-318), urotension II (V.Sauzeau et al., Circ. Res., 2001, 88, 1102-1104), endothelin-1 (P.Tangkijvanich et al., Hepatology, 2001, 33, 74-80), serotonin (H.Shimokawa, Jpn. Circ. J., 2000, 64, 1-12), norepinephrine (M. C.Martinez, et al., Am. J. Physiol., 2000, 279, H1228-H1238) andplatelet-derived growth factor (PDGF) (H. Kishi et al., J. Biochem.,2000, 128, 719-722). Many of these factors are implicated in thepathogenesis of cardiovascular disease.

Additional studies in the literature, some using the known ROCKinhibitors fasudil (T. Asano et al., J. Pharmacol. Exp. Ther., 1987,241, 1033-1040) or Y-27632 (M. Uehata et al., Nature, 1997, 389,990-994) further illustrate the link between ROCK and cardiovasculardisease. For example, ROCK expression and activity have been shown to beelevated in spontaneously hypertensive rats, suggesting a link to thedevelopment of hypertension in these animals (Y. Mukai et al., FASEB J.,2001, 15, 1062-1064). The ROCK inhibitor Y-27632 (M. Uehata et al.,Nature, ibid) was shown to significantly decrease blood pressure inthree rat models of hypertension, including the spontaneouslyhypertensive rat, renal hypertensive rat and deoxycortisone acetate salthypertensive rat models, while having only a minor effect on bloodpressure in control rats. This reinforces the link between ROCK andhypertension.

Other studies suggest a link between ROCK and atherosclerosis. Forexample, gene transfer of a dominant negative form of ROCK suppressedneointimal formation following balloon injury in porcine femoralarteries (Y. Eto et al., Am. J. Physiol. Heart Circ. Physiol., 2000,278, H1744-H1750). In a similar model, ROCK inhibitor Y-27632 alsoinhibited neointimal formation in rats (N. Sawada et al., Circulation,2000, 101, 2030-2033). In a porcine model of IL-1 beta-induced coronarystenosis, long term treatment with the ROCK inhibitor fasudil was shownto progressively reduce coronary stenosis, as well as promote aregression of coronary constrictive remodeling (H. Shimokawa et al.,Cardiovascular Res., 2001, 51, 169-177).

Additional investigations suggest that a ROCK inhibitor would be usefulin treating other cardiovascular diseases. For example, in a rat strokemodel, fasudil was shown to reduce both the infarct size and neurologicdeficit (Y. Toshima, Stroke, 2000, 31, 2245-2250). The ROCK inhibitorY-27632 was shown to improve ventricular hypertrophy, fibrosis andfunction in a model of congestive heart failure in Dahl salt-sensitiverats (N. Kobayashi et al. Cardiovascular Res., 2002, 55, 757-767).

Other animal or clinical studies have implicated ROCK in additionaldiseases including coronary vasospasm (H. Shimokawa et al., Cardiovasc.Res., 1999, 43, 1029-1039), cerebral vasospasm (M. Sato et al., Circ.Res., 2000, 87, 195-200), ischemia/reperfusion injury (T. Yada et al.,J. Am. Coll. Cardiol., 2505, 45, 599-607), pulmonary hypertension (Y.Fukumoto et al., Heart, 2005, 91, 391-392), angina (H. Shimokawa et al.,J. Cardiovasc. Pharmacol., 2002, 39, 319-327), renal disease (S. Satohet al., Eur. J. Pharmacol., 2002, 455, 169-174) and erectile dysfunction(N. F. Gonzalez-Cadavid and J. Rajifer, Endocrine, 2004, 23, 167-176).

In another study, it has been demonstrated that inhibition of theRhoA/ROCK signaling pathway allows formation of multiple competinglamellipodia that disrupt the productive migration of monocytes (R. A.Worthylake et al. The Journal of Biol. Chem., 2003, 278, 13578-13584).It has also been reported that small molecule inhibitors of Rho Kinaseare capable of inhibiting MCP-1 mediated chemotaxis in vitro (H. Iijima,Biorganic and Medicinal Chemistry, 2007, 15, 1022-1033). Due to thedependence of immune cell migration upon the RhoA/ROCK signaling pathwayone would anticipate inhibition of Rho Kinase should also providebenefit for diseases such as rheumatoid arthritis, psoriasis, andinflammatory bowel disease.

The above studies provide evidence for a link between ROCK andcardiovascular diseases including hypertension, atherosclerosis,restenosis, stroke, heart failure, coronary vasospasm, cerebralvasospasm, ischemia/reperfusion injury, pulmonary hypertension andangina, as well as renal disease and erectile dysfunction. Given thedemonstrated effect of ROCK on smooth muscle, ROCK inhibitors may alsobe useful in other diseases involving smooth muscle hyper-reactivity,including asthma and glaucoma (H. Shimokawa et al., Arterioscler.Thromb. Vase. Biol., 2005, 25, 1767-1775). Furthermore, Rho-kinase hasbeen indicated as a drug target for the treatment of various otherdiseases, including airway inflammation and hyperresponsiveness (P. J.Henry et al., Pulm Pharmacol Ther., 2005, 18, 67-74), cancer (R. Rattanet al., J Neurosci. Res., 2006, 83, 243-55. D. Lepley et al., CancerRes., 2005, 65, 3788-95), fibrotic diseases (C. Jiang, et. al., Int. J.Mol. Sci., 2012, 13, 8293-8307; L. Zhou, et. al., Am. J. Nephrol., 2011,34, 468-475), as well as neurological disorders, such as spinal-cordinjury, Alzheimer disease, multiple sclerosis, stroke and neuropathicpain (B. K. Mueller et al., Nat Rev Drug Disc, 2005, 4, 387-398; X. Sunet. al., J. Neuroimmunology, 2006, 180, 126-134).

There remains an unmet medical need for new drugs to treatcardiovascular disease. In the 2012 update of Heart Disease and StrokeStatistics from the American Heart Association (Circulation, 2012, 125,e2-e220), it was reported that cardiovascular disease accounted for32.8% of all deaths in the US, with coronary heart disease accountingfor ˜1 in 6 deaths overall in the US. Contributing to these numbers, itwas found that ˜33.5% of the adult US population was hypertensive, andit was estimated that in 2010 ˜6.6 million US adults would have heartfailure. Therefore, despite the number of medications available to treatcardiovascular diseases (CVD), including diuretics, beta blockers,angiotensin converting enzyme inhibitors, angiotensin blockers andcalcium channel blockers, CVD remains poorly controlled or resistant tocurrent medication for many patients.

Although there are many reports of ROCK inhibitors under investigation(see, for example, U.S. 20120122842 A1, U.S. 20100041645 A1, U.S.20080161297 A1, and E. Hu and D. Lee, Expert Opin. Ther. Targets, 2005,9, 715-736), fasudil is the only marketed ROCK inhibitor at this time.An i.v. formulation was approved in Japan for treatment of cerebralvasospasm. There remains a need for new therapeutics, including ROCKinhibitors, for the treatment of cardiovascular diseases, cancer,neurological diseases, renal diseases, fibrotic diseases, bronchialasthma, erectile dysfunction, and glaucoma.

SUMMARY OF THE INVENTION

The present invention provides novel phthalazinone and isoquinolinonecompounds, their analogues, including stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof, which are usefulas selective inhibitors of Rho kinases.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of conditions associated with aberrant ROCK activity.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a conditionassociated with aberrant ROCK activity.

In another aspect, the present invention is directed to a method oftreating a cardiovascular or related disease which method comprisesadministering to a patient in need of such treatment a compound of thepresent invention as described above. Examples of such diseases that maybe treated include, for example, hypertension, atherosclerosis,restenosis, stroke, heart failure, renal failure, coronary arterydisease, peripheral artery disease, coronary vasospasm, cerebralvasospasm, ischemia/reperfusion injury, pulmonary hypertension, angina,erectile dysfunction and renal disease.

In another aspect, the present invention is directed to a method oftreating diseases involving smooth muscle hyper reactivity includingasthma, erectile dysfunction and glaucoma, which method comprisesadministering to a patient in need of such treatment a compound of thepresent invention as described above.

In another aspect, the present invention is directed to a method oftreating diseases mediated at least partially by Rho kinase includingfibrotic diseases, oncology, spinal-cord injury, Alzheimer's disease,multiple sclerosis, stroke, neuropathic pain, rheumatoid arthritis,psoriasis and inflammatory bowel disease, which method comprisesadministering to a patient in need of such treatment a compound of thepresent invention as described above.

In yet additional aspects, the present invention is directed atpharmaceutical compositions comprising the above-mentioned compounds,processes for preparing the above-mentioned compounds and intermediatesused in these processes.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION

I. Compounds of the Invention

In one aspect, the present invention provides, inter alia, compounds ofFormula (I):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CR¹⁰;

L is selected from C₁₋₂ alkylene substituted with 1-2 R⁴, wherein atleast one carbon atom and the groups attached thereto are replaced by O,NR⁶, and C(O);

R¹ is selected from OC₁₋₄ alkyl, NR⁵R⁵, C₃₋₁₀ carbocycle and 4- to12-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycle,and heterocycle are substituted with 1-4 R⁷;

R², at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, carbocycle, andheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R³, at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, carbocycle, andheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁴, at each occurrence, is independently selected from H, halogen, OH,NH₂, CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), C₁₋₄ alkyl, carbocycle, and heterocycle, whereinsaid alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and —(CR⁶R⁶)_(n)-4-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p), wherein said alkyl, carbocycle and heterocycle are substitutedwith 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,—CH₂CONH₂, —(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂,—NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), and CONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halo, —OH,C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

provided

-   -   (1) when L is NHC(O), R¹ is other than

-   -    wherein X is N or a substituted or unsubstituted carbon atom;    -   (2) when L is NH, R¹ is other than

-   -   (3) when L is O, R¹ is other than

In another aspect, the present invention provides compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is selected from —CR⁴R⁴C(O)—, —OC(O)—, —NR⁶C(O)—, and —NR⁶—;

R⁴, at each occurrence, is independently selected from H and C₁₋₄ alkyl;and

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHC(O)NH₂, —NHC(O)NH(C₁₋₄alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄alkyl), —SO₂N(C₁₋₄ alkyl)₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p) whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹;

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(II):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CR¹⁰;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂—(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂,—NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), and CONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halo, —OH,C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(II) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵ is selected from H, C₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-4-10 membered heterocycle selected from

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(II) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form a heterocycle selected from

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(III):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CR¹⁰;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is —NR⁶—;

R¹ is selected from C₃₋₁₀ carbocycle and 5- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is —NR⁶—; and

R¹ is selected from

other variables are as defined in Formula (I) above.

In still another aspect, the present invention provides compounds ofFormula (IV):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle, and 5- to 10-memberedheterocycle, wherein said carbocycle and heterocycle are substitutedwith 1-4 R⁷;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (I) above.

In still another aspect, the present invention provides compounds ofFormula (IV), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

R¹ is selected from

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHC(O)NH₂,—NHC(O)NH(C₁₋₄ alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; and

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

other variables are as defined in Formula (I) above.

In still another aspect, the present invention provides compounds ofFormula (IV), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

R¹ is NR⁵R⁵;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; and

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(V):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is selected from C₁₋₂ alkylene substituted with 1-2 R⁴, wherein atleast one carbon atom and the groups attached thereto are replaced by O,NR⁶, and C(O);

R¹ is selected from OC₁₋₄ alkyl, NR⁵R⁵, C₃₋₁₀ carbocycle and 4- to12-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycle,and heterocycle are substituted with 1-4 R⁷;

R², at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, carbocycle, andheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R³, at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, carbocycle, andheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁴, at each occurrence, is independently selected from H, halogen, OH,NH₂, CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), C₁₋₄ alkyl, carbocycle, and heterocycle, whereinsaid haloalkyl, alkyl, alkoxy, carbocycle and heterocycle aresubstituted with 0-4 R⁹;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and —(CR⁶R⁶)_(n)-4-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p), wherein said alkyl, carbocycle and heterocycle are substitutedwith 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,—CH₂CONH₂, —(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂,—NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), and CONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halo, —OH,C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

provided

-   -   (1) when L is NHC(O), R¹ is other than

-   -    wherein X is N or a substituted or unsubstituted carbon atom;    -   (2) when L is NH, R¹ is other than

-   -   (3) when L is O, R¹ is other than

In another aspect, the present invention provides compounds of Formula(V) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is selected from —CR⁴R⁴C(O)—, —OC(O)—, —NR⁶C(O)—, and —NR⁶—;

R⁴, at each occurrence, is independently selected from H and C₁₋₄ alkyl;and

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHC(O)NH₂, —NHC(O)NH(C₁₋₄alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄alkyl), —SO₂N(C₁₋₄ alkyl)₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹;

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(VI):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂—(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂,—NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), and CONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halo, —OH,C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(VI) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵ is selected from H, C₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-4-10 membered heterocycle selected from

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(VI) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form a heterocycle selected from

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(VII):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(V) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is —NR⁶—;

R¹ is selected from C₃₋₁₀ carbocycle and 5- to 10-membered heterocycle,wherein said carbocycle and heterocycle are substituted with 1-4 R⁷;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(V) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is —NR⁶—; and

R¹ is selected from

other variables are as defined in Formula (V) above.

In still another aspect, the present invention provides compounds ofFormula (VIII):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle, and 5- to 10-memberedheterocycle, wherein said carbocycle and heterocycle are substitutedwith 1-4 R⁷;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (V) above.

In still another aspect, the present invention provides compounds ofFormula (VIII), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

R¹ is selected from

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; and

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

other variables are as defined in Formula (V) above.

In still another aspect, the present invention provides compounds ofFormula (VIII), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

R¹ is NR⁵R⁵;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; and

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, and heterocycle are substituted with 0-4R^(b);

other variables are as defined in Formula (V) above.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), and (IV), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein M is N or CR¹⁰; L is selected from —CR⁴R⁴C(O)—, —OC(O)—,—NR⁶C(O)—, and —NR⁶—; R¹ is selected from OC₁₋₄ alkyl, NR⁵R⁵, C₃₋₁₀carbocycle and 4- to 12-membered heterocycle comprising carbon atoms and1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p); wherein saidalkyl, carbocycle and heterocycle are substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, —NR⁶C(O)—, and—NR⁶—; R¹ is selected from OC₁₋₄ alkyl, NR⁵R⁵, C₃₋₁₀ carbocycle and 4-to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycleand heterocycle are substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (IV), (V), and (VIII), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein L is selected from —NR⁶C(O)—, and —NR⁶—; R¹ is 4- to 12-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p) and substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (IV), (V), and (VIII), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein L is selected from —NR⁶C(O)— or NR⁶—; R¹ is selected from

In one embodiment, the present invention provides compounds of Formulae(I), (IV), (V), and (VIII), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein L is selected from —NR⁶C(O)—, and —NR⁶—; R¹ is C₃₋₁₀ carbocyclesubstituted with 1-4 R⁷ substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (IV), (V), and (VIII), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein L is selected from —NR⁶C(O)—, and —NR⁶—; R¹ is C₃₋₆ cycloalkylsubstituted with 1-4 R⁷ or aryl substituted with 1-4 R⁷; R⁷, at eachoccurrence, is independently selected from H, ═O, halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl),—(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH,—NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹.

In one embodiment, the present invention provides compounds of Formulae(I), (IV), (V), and (VIII), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein L is selected from —NR⁶C(O)—, and —NR⁶—; R¹ is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or phenyl, each substituted with 1-4R⁷; R⁷, at each occurrence, is independently selected from H, ═O,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,—CH₂CONH₂, —(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is NR⁵R⁵; R⁵, at each occurrence, is independently selected from H,C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is NR⁵R⁵; R⁵, at each occurrence, is independently selected from H,C₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-4-10membered heterocycle selected

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is NR⁵R⁵; R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p),wherein said heterocycle is substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and NR⁶C(O)—;R¹ is NR⁵R⁵; R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,—CH₂CONH₂, —(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, —NR⁶C(O)—, and—NR⁶—; R¹ is selected from

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, —NR⁶C(O)—, and—NR⁶—; R¹ is selected from OC₁₋₄ alkyl, NR⁵R⁵, C₃₋₁₀ carbocycle and 4-to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycleand heterocycle are substituted with 1-4 R⁷; R⁵, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀carbocycle, and —(CR⁶R⁶)_(n)-4-10 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, carbocycle and heterocycle are substituted with 1-4 R⁷;alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, —NR⁶C(O)—, and—NR⁶—; R¹ is selected from OC₁₋₄ alkyl, C₃₋₁₀ carbocycle and 4- to12-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p); wherein said carbocycle andheterocycle are substituted with 1-4 R⁷; R⁵, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocyclesubstituted with 1-4 R⁷, and —(CR⁶R⁶)_(n)-4-10 membered heterocycleselected from

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds exemplified in the presentapplication.

In another embodiment, the compounds of the present invention have ROCKIC50 values ≦10 μM.

In another embodiment, the compounds of the present invention have ROCKIC50 values ≦1 μM.

In another embodiment, the compounds of the present invention have ROCKIC50 values ≦0.1 μM.

In another embodiment, the compounds of the present invention have ROCKIC50 values ≦0.05 μM.

In another embodiment, the compounds of the present invention have ROCKIC50 values ≦0.01 μM.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate, thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s).

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of a condition associated with aberrantROCK activity comprising administering to a patient in need of suchtreatment and/or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof. Asused herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a patient that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state. In another embodiment, the present inventionprovides a combined preparation of a compound of the present inventionand additional therapeutic agent(s) for simultaneous, separate orsequential use in therapy.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

II. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁-C₆ alkyl” denotes alkyl having 1 to 6carbon atoms. Alkyl group can be unsubstituted or substituted with atleast one hydrogen being replaced by another chemical group. Examplealkyl groups include, but are not limited to, methyl (Me), ethyl (Et),propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl,t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C₀alkyl” or “C₀ alkylene” is used, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example methyl-S—and ethyl-S—.

“Halo” or “halogen” includes fluoro (F), chloro (Cl), bromo (Br), andiodo (I). “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogens.Examples of haloalkyl include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl,pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, andheptachloropropyl. Examples of haloalkyl also include “fluoroalkyl” thatis intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more fluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclicor 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclichydrocarbon ring, any of which may be saturated, partially unsaturated,unsaturated or aromatic. Examples of such carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocycle” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary (13th Edition), J. Wiley &Sons, Inc., New York (1997). “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers tophenyl and naphthyl. Unless otherwise specified, “aryl”, “C₆ or C₁₀aryl” or “C₆₋₁₀ aryl” or “aromatic residue” may be unsubstituted orsubstituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH₃, Cl,F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃,S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

The term “benzyl,” as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic orbicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclicheterocyclic ring that is saturated, partially unsaturated, or fullyunsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; andincluding any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder,K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press(1985);

b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs,” ATextbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen,P. et al., eds., Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “saturated” for saturated, “MW” for molecularweight, “mp” for melting point, “ee” for enantiomeric excess, “MS” or“Mass Spec” for mass spectrometry, “ESI” for electrospray ionizationmass spectroscopy, “HR” for high resolution, “HRMS” for high resolutionmass spectrometry, “LCMS” for liquid chromatography mass spectrometry,“HPLC” for high pressure liquid chromatography, “RP HPLC” for reversephase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhausereffect spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

-   Me Methyl-   Et Ethyl-   Pr Propyl-   i-Pr Isopropyl-   Bu Butyl-   i-Bu Isobutyl-   t-Bu tert-butyl-   Ph Phenyl-   Bn Benzyl-   Boc tert-butyloxycarbonyl-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   AIBN Azobisisobutyronitrile-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate-   CBz Carbobenzyloxy-   CH₂Cl₂ Dichloromethane-   CH₃CN or ACN Acetonitrile-   CDCl₃ deutero-chloroform-   CHCl₃ Chloroform-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2 dichloroethane-   DCM dichloromethane-   DEA diethylamine-   Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or diisopropylethylamine-   Hunig's base-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)-EtDuPhosRh(I)    (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH Ethanol-   GMF glass microfiber filter-   Grubbs (II)    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid-   Hex Hexane-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂SO₄ sulfuric acid-   K₂CO₃ potassium carbonate-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH Methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ Ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl_(2 [)1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   POCl₃ phosphorus oxychloride-   i-PrOH or IPA isopropanol-   PS polystyrene-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAI tetra-n-butylammonium iodide-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   T3P propane phosphonic acid anhydride-   TRIS tris(hydroxymethyl)aminomethane

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis.

IV. Biology

In Vitro Assays

The effectiveness of compounds of the present invention as ROCKinhibitors can be determined in a 30 μL assay containing 20 mM HEPES, pH7.5, 20 mM MgCl₂, 0.015% Brij-35, 4 mM DTT, 5 μM ATP and 1.5 μM peptidesubstrate (FITC-AHA-AKRRRLSSLRA-OH). Compounds were dissolved in DMSO sothat the final concentration of DMSO was <2%, and the reaction wasinitiated with Rho kinase variants. After incubation, the reaction wasterminated by the addition of EDTA and the phosphorylated andnon-phosphorylated peptides separated using a LabChip 3000 Reader(Caliper Life Sciences). Controls consisted of assays that did notcontain compound, and backgrounds consisted of assays that containedenzyme and substrate but had EDTA from the beginning of the reaction toinhibit kinase activity. Compounds were tested in dose-response format,and the inhibition of kinase activity was calculated at eachconcentration of compound. The inhibition data were fit using acurve-fitting program to determine the IC₅₀; i.e., the concentration ofcompound required to inhibit 50% of kinase activity.”

Representative Examples were tested in the ROCK assay described aboveand found having ROCK inhibitory activity. A range of ROCK inhibitoryactivity (IC50 values) of ≦50 μM (50000 nM) was observed. Table A belowlists the ROCK IC50 values measured for the following examples.

TABLE A ROCK1 IC50 ROCK2 IC50 Example No. (nM) (nM) 2 679 30 10 729 1713 16200 9733 19 6482 5834 33 23 1.2 34 11940 553 48 670 39 52 544 22558 35 0.3 61 49 2.1 67 175 14 69 50000 894 76 20 1.2V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the patient to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 1000 mg/kg of body weight, preferably between about0.01 to about 100 mg/kg of body weight per day, and most preferablybetween about 0.1 to about 20 mg/kg/day. Intravenously, the mostpreferred doses will range from about 0.001 to about 10 mg/kg/minuteduring a constant rate infusion. Compounds of this invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

Compounds of this invention can also be administered by parenteraladministration (e.g., intra-venous, intra-arterial, intramuscularly, orsubcutaneously. When administered intra-venous or intra-arterial, thedose can be given continuously or intermittent. Furthermore, formulationcan be developed for intramuscularly and subcutaneous delivery thatensure a gradual release of the active pharmaceutical ingredient.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfate, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of ROCK. Such compounds may beprovided in a commercial kit, for example, for use in pharmaceuticalresearch involving ROCK. For example, a compound of the presentinvention could be used as a reference in an assay to compare its knownactivity to a compound with an unknown activity. This would ensure theexperimentor that the assay was being performed properly and provide abasis for comparison, especially if the test compound was a derivativeof the reference compound. When developing new assays or protocols,compounds according to the present invention could be used to test theireffectiveness.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a cardiovascular and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat cardiovascular and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The following Examples have been prepared, isolated andcharacterized using the methods disclosed herein.

VI. General Synthesis Including Schemes

The compounds of the present invention may be synthesized by methodsavailable to those skilled in the art of organic chemistry (Maffrand, J.P. et al., Heterocycles, 16(1):35-37 (1981)). General synthetic schemesfor preparing compounds of the present invention are described below.These schemes are illustrative and are not meant to limit the possibletechniques one skilled in the art may use to prepare the compoundsdisclosed herein. Different methods to prepare the compounds of thepresent invention will be evident to those skilled in the art.Additionally, the various steps in the synthesis may be performed in analternate sequence in order to give the desired compound or compounds.

Examples of compounds of the present invention prepared by methodsdescribed in the general schemes are given in the intermediates andexamples section set out hereinafter. Preparation of homochiral examplesmay be carried out by techniques known to one skilled in the art. Forexample, homochiral compounds may be prepared by separation of racemicproducts by chiral phase preparative HPLC. Alternatively, the examplecompounds may be prepared by methods known to give enantiomericallyenriched products. These include, but are not limited to, theincorporation of chiral auxiliary functionalities into racemicintermediates which serve to control the diastereoselectivity oftransformations, providing enantio-enriched products upon cleavage ofthe chiral auxiliary.

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,4th Edition, Wiley-Interscience (2006)).

Scheme 1 shows the synthesis of generic compounds 1e, 1f, 1g, from thecommon intermediate 1d. Suzuki-Miyaura coupling between aryl halide 1aand boronic acid or boronate ester (1b) in the presence of a base suchas K₃PO₄ and a catalyst such as Pd(PPh₃)₄ affords intermediate 1c.Cleavage of the protecting group, such as using TFA or HCl in dioxanewhen PG=Boc, affords the arylamine intermediate 1d. Intermediate 1d isconverted to the urea target 1e by treatment with an isocyanate or acarbamic chloride. Intermediate 1d is converted to the amide target 1fby treatment with an acid chloride in the presence of a base such aspyridine or DIEA. Alternatively, Target 1f is prepared by coupling ofintermediate 1d with a carboxylic acid in the presence of a couplingreagent, such as HATU or BOP, and a base such as DIEA. Intermediate 1dis converted to the carbamate target 1g by treatment with achloroformate in the presence of a base such as DIEA or TEA.

Alternatively, targets 1e-g can be prepared as shown in Scheme 2. Arylhalide 2a (commercially available or prepared by literature methods) isconverted to the aryl boronic acid or boronate ester 2b by coupling withbis(pinacolato)diboron in the presence of a base such a potassiumacetate and a catalyst such as PdCl₂(dppf) in dioxane or DMSO.Suzuki-Miyaura coupling between aryl halide 1a and boronic acid orboronate ester (2b) in the presence of a base such as K₃PO₄ and acatalyst such as Pd(PPh₃)₄ affords target compounds 1e-g.

Alternatively, target 1e can be prepared as shown in Scheme 3 beginningfrom isocyanate 3a, which is either commercially available or can beprepared from the aniline precursor upon treatment with phosgene (orequivalent) and an appropriate base such as TEA. Intermediate 3a isreacted with amine (3b) to afford urea 3c. Suzuki-Miyaura couplingbetween aryl halide 1a and boronic acid or boronate ester (3c) in thepresence of a base such as K₃PO₄ and a catalyst such as Pd(PPh₃)₄affords target compounds 1e.

Scheme 4 shows the synthesis of carbamate target 4e, beginning fromchloroformate 4a (either commercially available or prepared by treatmentof an appropriate halophenol with phosgene or a phosgene equivalent).Intermediate 4a is reacted with an amine (4b) in the presence of a basesuch as TEA to afford carbamate 4c. Aryl halide 4c is converted to thearyl boronic acid or boronate ester 4d by coupling withbis(pinacolato)diboron in the presence of a base such a potassiumacetate and a catalyst such as PdCl₂(dppf) in dioxane or DMSO.Suzuki-Miyaura coupling between aryl halide 1a and boronic acid orboronate ester (4d) in the presence of a base such as K₃PO₄ and acatalyst such as Pd(PPh₃)₄ affords target compound 4e.

Scheme 5 shows the synthesis of amide target 5e, beginning with boronicacid/ester 5a, which is either commercially available or is preparedfrom the aryl halide precursor. Suzuki-Miyaura coupling between arylhalide 1a and boronic acid or boronate ester (5a) in the presence of abase such as K₃PO₄ and a catalyst such as Pd(PPh₃)₄ affords intermediate5b. Cleavage of the protecting group (PG) by alkaline hydrolysis (orother reagents as appropriate) affords carboxylic acid 5c. Coupling ofintermediate 5c with amine 5d in the presence of a coupling reagent,such as HATU or BOP, and a base such as DIEA affords target 5e.

Scheme 6 shows an alternate synthesis to target 5e beginning from acid6a. Coupling of intermediate 6a with amine 6b in the presence of acoupling reagent, such as HATU or BOP, and a base such as DIEA affordsintermediate amide 6c. Aryl halide 6c is converted to the aryl boronicacid or boronate ester 6d by coupling with bis(pinacolato)diboron in thepresence of a base such a potassium acetate and a catalyst such asPdCl₂(dppf) in dioxane or DMSO. Suzuki-Miyaura coupling between arylhalide 1a and boronic acid or boronate ester (6d) in the presence of abase such as K₃PO₄ and a catalyst such as Pd(PPh₃)₄ affords targetcompound 5e.

Scheme 7 shows the synthesis of target 7b beginning with intermediateaniline 1d. Aniline 1d is coupled with heteroaryl halide 7a underthermal S_(N)Ar conditions in the presence of a base such as DIEA in asolvent such as DMF to afford 7b. Alternatively, 1d and 7 a may becoupled under Buchwald-Hartwig N-arylation conditions using a base suchas Cs₂CO₃, a catalyst such as Pd₂(dba)₃ and an appropriate ligand toafford 7b.

Scheme 8 shows an alternative synthesis of target 7b, beginning fromintermediate 8a, which is either commercially available or can beprepared by literature methods. An appropriate protecting group isintroduced by treatment with a base such as potassium carbonate and aprotecting group reagent such as para-methoxybenzyl chloride to afford8b. Treatment of aryl bromide 8b with sodium azide, Cu₂O and a ligandsuch as proline affords aniline 8c. Aniline 8c is coupled withheteroaryl halide 7a under thermal S_(N)Ar conditions in the presence ofa base such as DIEA in a solvent such as DMF to afford intermediate 8d.Alternatively, 8c and 7a may be coupled under Buchwald-HartwigN-arylation conditions using a base such as Cs₂CO₃, a catalyst such asPd₂(dba)₃ and an appropriate ligand to afford intermediate 8d. Cleavageof the protecting group under appropriate conditions (TFA in the case ofa para-methoxybenzyl protecting group) affords target 7b.

Scheme 9 shows an alternative synthesis of target 7b, starting from arylbromide 8b. Coupling of intermediate 8b with heteroaryl amine 9a underBuchwald-Hartwig N-arylation conditions using a base such as Cs₂CO₃, acatalyst such as Pd₂(dba)₃ and an appropriate ligand affordsintermediate 8d. Cleavage of the protecting group under appropriateconditions (TFA in the case of a para-methoxybenzyl protecting group)affords target 7b.

Scheme 10 shows the synthesis of intermediate 1a, where X═N.Furan-2,5-dione 10a can be converted to intermediate 10b by treatmentwith a reagent such as hydrazine. Intermediate 10b is chlorinated bytreatment with a reagent such as POCl₃ to afford dichloro intermediate10c. Partial hydrolysis of 10c with a reagent such as AcOH affordsintermediate 1a.

Scheme 11 shows the synthesis of intermediate 1a, where X═CR.Intermediate 11a is brominated with a reagent such as NBS to affordintermediate 1a.

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out using prepacked SiO₂ cartridges elutingwith either gradients of hexanes and EtOAc or DCM and MeOH unlessotherwise indicated. Reverse phase preparative HPLC was carried outusing C18 columns eluting with gradients of Solvent A (90% H₂O, 10%MeOH, 0.1% TFA) and Solvent B (10% H₂O, 90% MeOH, 0.1% TFA, UV 220 nm)or with gradients of Solvent A (90% H₂O, 10% ACN, 0.1% TFA) and SolventB (10% H₂O, 90% ACN, 0.1% TFA, UV 220 nm) or with gradients of Solvent A(98% H₂O, 2% ACN, 0.05% TFA) and Solvent B (98% ACN, 2% H₂O, 0.05% TFA,UV 220 nm) (or) Sunfire Prep C18 OBD 5u 30×100 mm, 25 min gradient from0-100% B. A=H₂O/ACN/TFA 90:10:0.1. B=ACN/H₂O/TFA 90:10:0.1 (or) WatersXBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Solvent A: water with 20-mM ammoniumacetate; Solvent B: 95:5 acetonitrile:water with 20-mM ammonium acetate;Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min.

Unless otherwise stated, analysis of final products was carried out byreverse phase analytical HPLC.

Method A: Sunfire C18 column (3.5 μm C18, 3.0×150 mm) Gradient elution(1.0 mL/min) from 10-100% Solvent B over 10 min and then 100% Solvent Bfor 5 mM was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA)and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).

Method B: XBridge Phenyl column (3.5 μm C18, 3.0×150 mm) Gradientelution (1.0 mL/min) from 10-100% Solvent B over 10 min and then 100%Solvent B for 5 mM was used. Solvent A is (95% water, 5% acetonitrile,0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV254 nm).

Method C: Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40°C.; Gradient 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a0.5-minute hold at 100% B; Flow: 1 mL/min.

Method D: Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A:5:95 methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10 mM ammonium acetate; Temperature: 40° C.;Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a0.5-minute hold at 100% B; Flow: 0.5 mL/min.

Method E: Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100%B over 3 minutes; Flow: 1.11 mL/min.

Method F: Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 minutes; Flow: 1.11 mL/min.

INTERMEDIATE 1 2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetic acid

INTERMEDIATE 1A ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a vial containing a degassed (3× vacuum/Ar) mixture of ethyl2-(4-bromophenyl)acetate (1 g, 4.11 mmol), bis(pinacolato)diboron (1.25g, 4.94 mmol), and potassium acetate (1.21 g, 12.3 mmol) in dioxane (10mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (0.090 g, 0.123 mmol). Thereaction mixture was degassed, sealed and heated at 110° C. for 16 h.The mixture was diluted with water, then extracted with EtOAc. Theorganic phase was concentrated and purified via flash chromatography(EtOAc/hexane) to afford 1.1 g (92%) of Intermediate 1A.

MS (ESI) m/z: 291.2 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.84-7.71 (m, 2H),7.34-7.28 (m, J=8.0 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 1.27(s, 12H), 1.26-1.22 (m, 3H).

INTERMEDIATE 1B ethyl2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetate

To 4-chlorophthalazin-1(2H)-one (200 mg, 1.11 mmol), Intermediate 1A(386 mg, 1.33 mmol) and K₃PO₄ (588 mg, 2.77 mmol), were added dioxane (9mL) and water (1 mL). The mixture was degassed (evacuated and flushedwith Ar (5×)). Pd(PPh₃)₄ (64.0 mg, 0.055 mmol) was added, then themixture was degassed (2×). The reaction vial was sealed and heated in amicrowave reactor at 150° C. for 30 min. The reaction mixture wasconcentrated and purified via flash chromatography (EtOAc/hexane) toafford 218 mg (46%) of Intermediate 1B.

MS (ESI) m/z: 309.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (s, 1H),8.46-8.28 (m, 1H), 7.99-7.82 (m, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.59-7.54(m, 2H), 7.45 (d, J=6.6 Hz, 2H), 4.12 (qd, J=7.1, 1.8 Hz, 2H), 3.79 (s,2H), 1.22 (td, J=7.0, 1.9 Hz, 3H).

INTERMEDIATE 1

To a solution of Intermediate 1B (210 mg, 0.681 mmol) in MeOH (5 mL) andTHF (5 mL), was added 1M aq. lithium hydroxide (3.41 mL, 3.41 mmol). Themixture was stirred rt overnight, then was concentrated. The residue wasacidified with TFA, then was dissolved in DMSO/MeOH, and purifiedpreparative HPLC to afford 170 mg (89%) of Intermediate 1.

MS (ESI) m/z: 281.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H),8.42-8.21 (m, 1H), 7.99-7.82 (m, 2H), 7.77-7.62 (m, 1H), 7.59-7.50 (m,2H), 7.49-7.37 (m, J=8.3 Hz, 2H), 3.69 (s, 2H).

INTERMEDIATE 2 5-((4-methylpiperazin-1-yl)methyl)isoindoline, 3 TFA

INTERMEDIATE 2A tert-butyl di(prop-2-yn-1-yl)carbamate

To a solution of 2-Propyn-1-amine and N-2-propynyl- (1.110 mL, 10.74mmol) in THF (20 mL) at rt, was added BOC₂O (2.58 g, 11.81 mmol). Tothis mixture was added TEA (0.150 mL, 1.074 mmol). The mixture wasstirred at rt for 14 h. The reaction mixture was concentrated to an oil.The oil was partitioned between 0.2 N HCl and EtOAc. The organic phasewas washed with H₂O, sat. NaHCO₃ and brine, dried (Na₂SO₄), filteredthrough a 1″ pad of SiO₂ and concentrated to afford 2.40 g (100%) ofIntermediate 2A as a yellow oil.

MS (ESI) m/z: 216.1 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 4.17 (br. s., 4H),2.22 (t, J=2.4 Hz, 2H), 1.48 (s, 9H).

INTERMEDIATE 2B tert-butyl 5-(hydroxymethyl)isoindoline-2-carboxylate

To a degassed (evacuated and flushed with Ar (5×)) solution ofprop-2-yn-1-ol (0.961 mL, 16.11 mmol) in toluene (5 mL) at 50° C., wereadded in 5 portions at 10 minute intervals Intermediate 2A (1.20 g, 5.37mmol) in degassed toluene (5 mL) and Tris(triphenylphosphine)rhodium(I)chloride (0.124 g, 0.134 mmol). Following the last addition, the brownmixture was stirred at 50° C. for 1.25 h. The reaction mixture wasconcentrated, then was co-evaporated with CHCl₃ (2×). The crude productwas purified by flash chromatography (0 to 100% ethyl acetate/hexanes,eluted at 75% EtOAc) to afford 1.15 g (86% yield) of Intermediate 2B asa white solid.

MS (ESI) m/z: 521.3 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.33-7.21 (m, 3H),4.63 (dd, J=5.6, 3.2 Hz, 4H), 4.60 (s, 2H), 1.52 (s, 9H).

INTERMEDIATE 2C tert-butyl5-(((methylsulfonyl)oxy)methyl)isoindoline-2-carboxylate

To a solution of Intermediate 2B (500 mg, 2.006 mmol) in DCM (10 mL) at0° C., were added DIEA (0.420 mL, 2.407 mmol) and Ms-Cl (0.172 mL, 2.206mmol). The mixture was stirred at 0° C. for 1.5 h. The mixture wasdiluted with DCM, then was washed with half sat. NH₄Cl and brine. Theorganic phase was dried (Na₂SO₄) and concentrated to afford 655 mg(100%) of Intermediate 2C as a brown oil. The material was used in thefollowing step without further purification.

MS (ESI) m/z: 272.0 (M−t-Bu+2H)⁺

INTERMEDIATE 2D tert-butyl5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate

To a solution of Intermediate 2C (657 mg, 2.007 mmol) in acetone (10 mL)at rt, were added K₂CO₃ (416 mg, 3.01 mmol) and 1-methyl piperazine(0.556 mL, 5.02 mmol). The mixture was stirred at rt for 2.5 h, then 1 hat 50° C. The mixture was concentrated, then was partitioned betweenEtOAc and H₂O. The aqueous phase was extracted with EtOAc (2×). Thecombined organic phase was dried (Na₂SO₄) and concentrated to affordIntermediate 2D as a brown oil.

MS (ESI) m/z: 332.2 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.30-7.21 (m, 3H),4.63 (dd, J=5.5, 2.0 Hz, 4H), 3.53 (s, 2H), 2.50 (br. s., 8H), 2.27 (s,3H), 1.52 (s, 9H)

INTERMEDIATE 2

Intermediate 2D was treated with 4N HCl in dioxane (5 mL, 20.00 mmol)and the resultant suspension was stirred for 1 h, then was concentrated.The mixture was redissolved in TFA (10 mL) and was stirred at rt for 20min. The mixture was concentrated. The brown oil was coevaporated withDCM (2×), ether, MeOH and CH₃CN to afford 1.36 g (100% yield, ˜85%purity) of Intermediate 2 as a brown semisolid, which was used as iswithout further purification.

MS (ESI) m/z: 232.2 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.49-7.40 (m, 3H),4.62 (s, 4H), 3.82 (s, 2H), 3.34 (br. s., 4H), 2.89 (s, 3H), 2.90 (br.s, 4H)

INTERMEDIATE 3 4-(4-aminophenyl)phthalazin-1(2H)-one, TFA salt

INTERMEDIATE 3A tert-butyl(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

To 4-chlorophthalazin-1(2H)-one (118 mg, 0.653 mmol),(4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (170 mg, 0.719 mmol)and potassium phosphate (347 mg, 1.634 mmol), were added dioxane (9 mL)and water (1 mL). The mixture was degassed (evacuated and flushed withAr (5×)). Pd(PPh₃)₄ (37.8 mg, 0.033 mmol) was added, then the mixturewas degassed (2×). The reaction vial was sealed and heated in amicrowave reactor at 150° C. for 35 min. The reaction mixture wasconcentrated and purified via flash chromatography to afford 150 mg(68%) of Intermediate 3A.

MS (ESI) m/z: 338.1 (M+H)⁺.

INTERMEDIATE 3

To Intermediate 3A (150 mg, 0.445 mmol) in CH₂Cl₂ (3 mL), was added TFA(2 mL). The mixture was stirred rt for 2 h, then was concentrated. Thecrude product was purified via flash chromatography, then preparativeHPLC to afford 62 mg (59%) of Intermediate 3.

MS (ESI) m/z: 238.1 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD) δ 8.44 (dt, J=4.7,2.3 Hz, 1H), 7.97-7.87 (m, 2H), 7.81-7.75 (m, 1H), 7.71-7.61 (m, 2H),7.41-7.30 (m, 2H)

INTERMEDIATE 42-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(isoindolin-2-yl)ethanone

INTERMEDIATE 4A 2-(4-bromo-2-fluorophenyl)-1-(isoindolin-2-yl)ethanone

To 2-(4-bromo-2-fluorophenyl)acetic acid (300 mg, 1.287 mmol),isoindoline (0.161 mL, 1.416 mmol), and HATU (587 mg, 1.545 mmol) in DMF(5 mL), was added DIEA (0.450 mL, 2.57 mmol). The mixture was stirred atrt for 1 h. The resultant heterogeneous mixture was diluted with EtOAc,then was washed with H₂O, 1N HCl, H₂O, sat. NaHCO₃ and brine. Theorganic phase was dried (Na₂SO₄), filtered and concentrated. The crudeproduct was purified by flash chromatography (gradient from 0 to 100%ethyl acetate/hexanes) to afford 147 mg (34%) of Intermediate 4A as awhite solid.

MS (ESI) m/z: 333.9 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.30 (m, 3H),7.30-7.22 (m, 4H), 4.89 (s, 2H), 4.83 (s, 2H), 3.73 (s, 2H)

INTERMEDIATE 4

To a mixture of Intermediate 4A (146 mg, 0.437 mmol),bis(pinacolato)diboron (133 mg, 0.524 mmol), and potassium acetate (129mg, 1.31 mmol) in a reaction vial, was added dioxane (3 mL). The mixturewas degassed (evacuated and flushed with Ar (3×)). PdCl₂(dppf) CH₂Cl₂adduct (9.6 mg, 0.013 mmol) was added, then reaction mixture wasdegassed (3× vacuum/Ar). The vial was sealed, then was heated at 110° C.for 2 h. The reaction mixture was diluted with EtOAc, then was washedwith H₂O and brine. The organic phase was dried (Na₂SO₄) andconcentrated. The crude product was purified by flash chromatography(gradient from 0 to 50% ethyl acetate/hexanes) to afford 120 mg (72%) ofIntermediate 4 as a yellow solid.

MS (ESI) m/z: 386.1 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, J=7.5,0.9 Hz, 1H), 7.50 (d, J=10.1 Hz, 1H), 7.39 (t, J=7.4 Hz, 1H), 7.32-7.22(m, 4H), 4.84 (s, 4H), 3.80 (s, 2H), 1.33 (s, 12H)

INTERMEDIATE 52-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(isoindolin-2-yl)ethanone

INTERMEDIATE 5A 2-(4-bromo-3-fluorophenyl)-1-(isoindolin-2-yl)ethanone

To a mixture of 2-(4-bromo-3-fluorophenyl)acetic acid (300 mg, 1.287mmol), isoindoline (0.161 mL, 1.416 mmol), and HATU (734 mg, 1.931 mmol)in DMF (5 mL), was add DIEA (0.450 mL, 2.6 mmol). The mixture wasstirred rt for 18 h. The reaction mixture was diluted with EtOAc, thenwas washed with H₂O, 1N HCl, H₂O, sat. Na₂CO₃ and brine. The organicphase was dried (Na₂SO₄), filtered through a 1″ pad of SiO₂ andconcentrated. The crude product was purified by flash chromatography(gradient from 0 to 100% ethyl acetate/hexanes) to afford 379 mg (88%)of Intermediate 5A as an off-white solid. MS (ESI) m/z: 333.9 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃) δ 7.50 (dd, J=8.0, 7.4 Hz, 1H), 7.33-7.22 (m, 4H),7.14 (dd, J=9.2, 2.0 Hz, 1H), 7.01 (dd, J=8.5, 1.9 Hz, 1H), 4.83 (s,4H), 3.72 (s, 2H)

INTERMEDIATE 5

To a mixture of Intermediate 5A (200 mg, 0.598 mmol),bis(pinacolato)diboron (182 mg, 0.718 mmol), and potassium acetate (176mg, 1.80 mmol) in a reaction vial, was added dioxane (5 mL). The mixturewas degassed (evacuated and flushed with Ar (3×)). PdCl₂(dppf) CH₂Cl₂adduct (13 mg, 0.018 mmol) was added, then the reaction mixture wasdegassed (3× vacuum/Ar). The vial was sealed, then was heated at 110° C.for 2 h. Additional catalyst (13 mg) was added and the reaction mixturewas stirred at 110° C. for 2 more hours. The reaction mixture was cooledto room temperature, then was filtered and concentrated. The crudeproduct was purified by flash chromatography (gradient from 0 to 100%ethyl acetate/hexanes) to afford 208 mg (91%) of Intermediate 5 as ayellow solid.

MS (ESI) m/z: 386.1 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.71 (t, J=6.9 Hz,1H), 7.35-7.20 (m, 4H), 7.13 (d, J=7.5 Hz, 1H), 7.04 (d, J=10.1 Hz, 1H),4.83 (s, 2H), 4.77 (s, 2H), 3.78 (s, 2H), 1.35 (s, 12H).

INTERMEDIATE 6 4-bromoisoquinolin-1(2H)-one

To a solution of isoquinolin-1(2H)-one (105 mg, 0.723 mmol) in DMF (2mL), was added NBS (142 mg, 0.796 mmol). The mixture was stirred at rtfor 2 h, then was concentrated. The crude product was purified viapreparative HPLC to afford 110 mg (68%) of Intermediate 6.

MS (ESI) m/z: 223.9 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.57 (br. s.,1H), 8.24 (dd, J=8.0, 0.8 Hz, 1H), 7.88-7.83 (m, 1H), 7.79-7.75 (m, 1H),7.61 (ddd, J=8.0, 7.1, 1.1 Hz, 1H), 7.55 (s, 1H).

INTERMEDIATE 7 2-(4-bromophenyl)-1-(isoindolin-2-yl)ethanone

To a mixture of 2-(4-bromophenyl)acetic acid (300 mg, 1.395 mmol),isoindoline (183 mg, 1.535 mmol), and HATU (796 mg, 2.093 mmol) in DMF(5 mL), was add DIEA (0.487 mL, 2.79 mmol). The mixture was stirred atrt overnight. The reaction mixture was quenched with water, thenextracted with EtOAc. The organic phase was washed with 10% LiCl, brine,and concentrated. The residue was purified via flash chromatography(EtOAc/hexane) to afford 390 mg (88%) of Intermediate 7.

MS (ESI) m/z: 316.0 (M+H)⁺.

INTERMEDIATE 8 (4-(2-(isoindolin-2-yl)acetyl)phenyl)boronic acid

A mixture of Intermediate 7 (30 mg, 0.095 mmol), bis(pinacolato)diboron(24 mg, 0.095 mmol), and potassium acetate (27.9 mg, 0.285 mmol) indioxane (1 mL) was degassed (3× vacuum/Ar). Then PdCl₂(dppf) CH₂Cl₂adduct (2.083 mg, 2.85 μmol) was added, the reaction mixture wasdegassed again (3× vacuum/Ar), sealed in a vial and heated at 110° C.for 2 h. The reaction was purified via preparative HPLC to afford 14 mg(53%) of Intermediate 8.

MS (ESI) m/z: 282.1 (M+H)⁺.

INTERMEDIATE 91-(isoindolin-2-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone

According to a procedure similar to the preparation of Intermediate 8,Intermediate 7 (400 mg, 1.27 mmol) afforded after flash chromatography(0 to 60% EtOAc/hexane gradient) 406 mg (88%) of Intermediate 9.

MS (ESI) m/z: 364.1 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.82-7.77 (m,J=8.3 Hz, 2H), 7.39-7.33 (m, J=8.0 Hz, 2H), 7.27 (d, J=0.6 Hz, 3H),7.27-7.24 (m, 1H), 7.20 (d, J=6.6 Hz, 1H), 4.84 (s, 2H), 4.77 (s, 2H),3.81 (s, 2H), 1.38-1.31 (m, 12H).

INTERMEDIATE 10N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)indoline-1-carboxamide

INTERMEDIATE 10A N-(4-bromophenyl)indoline-1-carboxamide

A mixture of 1-bromo-4-isocyanatobenzene (300 mg, 1.515 mmol) andindoline (199 mg, 1.667 mmol) in CH₂Cl₂ (5 mL) was stirred at rt 1 h.The reaction mixture was diluted with EtOAc (100 mL), then was washedwith 1N HCl, sat. Na₂CO₃, and brine. The organic phase was dried overNa₂SO₄, then concentrated. The residue was purified by flashchromatography (0-60% EtOAc/hexane gradient) to afford 470 mg (98%) ofIntermediate 10A as a yellow foam.

MS (ESI) m/z: 317.0 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J=8.0 Hz,1H), 7.49-7.42 (m, 2H), 7.41-7.35 (m, 2H), 7.22-7.17 (m, 2H), 6.99 (td,J=7.4, 1.1 Hz, 1H), 6.47 (br. s., 1H), 4.15-4.05 (m, 2H), 3.25 (t, J=8.5Hz, 2H)

INTERMEDIATE 10

To a mixture of Intermediate 10A (470 mg, 1.482 mmol),bis(pinacolato)diboron (452 mg, 1.778 mmol), and potassium acetate (436mg, 4.45 mmol) in dioxane (20 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct(32.5 mg, 0.044 mmol). The reaction mixture was degassed (3× vacuum/Ar),sealed in a vial and heated at 110° C. for 3 h. The reaction wasquenched with water, extracted with EtOAc (2×30 mL). The combinedorganic layer was washed with brine, dried (Na₂SO₄) and concentrated.The residue was purified by flash chromatography (0-60% EtOAc/hexanegradient) to afford 430 mg (80%) of Intermediate 10 as a white solid.

MS (ESI) m/z: 365.1 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J=8.0 Hz,1H), 7.81-7.77 (m, J=8.3 Hz, 2H), 7.52-7.48 (m, 2H), 7.23-7.18 (m, 2H),7.01-6.94 (m, 1H), 6.56 (s, 1H), 4.17-4.04 (m, 2H), 3.25 (t, J=8.5 Hz,2H), 1.39-1.32 (m, 12H).

INTERMEDIATE 11 2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propanoicacid

INTERMEDIATE 11A ethyl 2-(4-bromophenyl)propanoate

To a solution of ethyl 2-(4-bromophenyl)acetate (150 mg, 0.617 mmol) inTHF (3 mL) at −78° C., was added 1.5M LDA (0.514 mL, 0.926 mmol). Themixture was stirred at −78° C. for 20 min, then iodomethane (175 mg,1.23 mmol) was added. The solution was allowed to warm to rt and stirredover night. The reaction mixture was concentrated and the residue waspurified by flash chromatography (0-20% EtOAc/hexane gradient) to afford120 mg (76%) of Intermediate 11A as a yellow oil.

MS (ESI) m/z: 257.0 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.47-7.42 (m, 2H),7.21-7.16 (m, 2H), 4.12 (dddd, J=17.6, 10.4, 7.1, 3.7 Hz, 2H), 3.67 (q,J=7.3 Hz, 1H), 1.48 (d, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H)

INTERMEDIATE 11B ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

To a mixture of Intermediate 11A (120 mg, 0.467 mmol),bis(pinacolato)diboron (142 mg, 0.56 mmol), and potassium acetate (137mg, 1.40 mmol) in dioxane (4 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct(10 mg, 0.014 mmol). The reaction mixture was degassed (3× vacuum/Ar),sealed and heated at 110° C. for 16 h. The reaction mixture wasconcentrated and the residue was purified by flash chromatography (0-30%EtOAc/hexane gradient) to afford 120 mg (85%) of Intermediate 11B as ayellow oil.

MS (ESI) m/z: 327.2 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.81-7.75 (m,J=8.3 Hz, 2H), 7.35-7.29 (m, J=8.0 Hz, 2H), 4.11 (dddd, J=17.8, 10.6,7.1, 3.6 Hz, 2H), 3.77-3.66 (m, 1H), 1.49 (d, J=7.2 Hz, 3H), 1.37-1.30(m, 12H), 1.19 (t, J=7.2 Hz, 3H)

INTERMEDIATE 11C ethyl2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propanoate

To 4-chlorophthalazin-1(2H)-one (70 mg, 0.388 mmol), Intermediate 11B(118 mg, 0.388 mmol) and potassium phosphate (206 mg, 0.969 mmol), wereadded dioxane (3 mL) and water (0.333 mL). The mixture was degassed(evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (22.40 mg, 0.019 mmol)was added, then the mixture was degassed (2×). The reaction vial wassealed and heated in a microwave reactor at 150° C. for 30 min. Thereaction mixture was concentrated and the residue was purified by flashchromatography (0-80% EtOAc/hexane gradient) to afford 100 mg (80%) ofIntermediate 11C as a yellow foam.

MS (ESI) m/z: 323.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (s, 1H),8.41-8.31 (m, 1H), 7.98-7.84 (m, 2H), 7.70 (d, J=7.7 Hz, 1H), 7.57 (d,J=8.3 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 4.20-4.02 (m, 2H), 3.91 (d, J=6.9Hz, 1H), 1.46 (d, J=7.2 Hz, 3H), 1.17 (t, J=7.0 Hz, 3H).

Intermediate 11

To a solution of Intermediate 11C (100 mg, 0.310 mmol) in THF (3 mL),was added 1M LiOH (0.620 mL, 0.620 mmol). The mixture was stirred at rtfor 3 h, then was concentrated. The residue was purified via preparativeHPLC to afford 90 mg (99%) of Intermediate 11 as a white solid.

MS (ESI) m/z: 295.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H),8.42-8.23 (m, 1H), 7.99-7.82 (m, 2H), 7.78-7.66 (m, 1H), 7.61-7.52 (m,J=8.0 Hz, 2H), 7.50-7.40 (m, J=8.0 Hz, 2H), 3.80 (q, J=7.2 Hz, 1H), 1.44(d, J=6.9 Hz, 3H).

EXAMPLE 14-(4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

To 4-chlorophthalazin-1(2H)-one (9.9 mg, 0.055 mmol), Intermediate 8 (14mg, 0.050 mmol) and potassium phosphate (26.4 mg, 0.125 mmol), wereadded dioxane (3 mL) and water (0.5 mL). The mixture was degassed(evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (2.9 mg, 2.5 μmol) wasadded, then the mixture was degassed (2×). The reaction vial was sealedand heated in a microwave reactor at 150° C. for 25 min. The reactionmixture was concentrated, then was purified by preparative HPLC toafford 4.4 mg (18%) of Example 1.

MS (ESI) m/z: 382.20 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H),8.42-8.29 (m, 1H), 7.96-7.84 (m, 2H), 7.77-7.67 (m, 1H), 7.61-7.52 (m,2H), 7.52-7.43 (m, 2H), 7.41-7.36 (m, 2H), 7.36-7.27 (m, 2H), 4.98 (s,2H), 4.70 (s, 2H), 3.89 (s, 2H); Analytical HPLC RT=1.51 min (Method E),1.52 min (Method F).

EXAMPLE 24-(4-(2-(5-fluoroisoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

According a method similar to the preparation of Example 1, substitutionof isoindoline with 5-fluoroisoindoline afforded Example 2.

MS (ESI) m/z: 400.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H),8.38-8.31 (m, 1H), 7.93-7.86 (m, 2H), 7.74-7.69 (m, 1H), 7.66-7.36 (m,5H), 7.23 (d, J=9.1 Hz, 1H), 7.18-7.10 (m, 1H), 4.95 (d, J=16.8 Hz, 2H),4.68 (d, J=16.8 Hz, 2H), 3.87 (s, 2H); Analytical HPLC RT=1.53 min(Method E), 1.52 min (Method F).

EXAMPLE 34-(4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

To a solution of Intermediate 1 (25 mg, 0.089 mmol) in DMF (3 mL), wasadded 5-methoxyisoindoline (20 mg, 0.134 mmol), PyBOP (69.6 mg, 0.134mmol), and DIEA (0.078 mL, 0.446 mmol). The mixture was stirred at rtfor 2 h, then was purified by preparative HPLC to afford 28.1 mg (59%)of Example 3.

MS (ESI) m/z: 412.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H),8.36-8.31 (m, 1H), 7.93-7.86 (m, 2H), 7.73-7.68 (m, 1H), 7.55 (d, J=7.7Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.26 (dd, J=8.3, 4.4 Hz, 1H), 6.95 (d,J=11.6 Hz, 1H), 6.88 (dd, J=8.4, 1.8 Hz, 1H), 4.95-4.86 (m, 2H),4.69-4.59 (m, 2H), 3.87 (s, 2H), 3.75 (s, 3H); Analytical HPLC RT=1.61min (Method E), 1.61 min (Method F).

The following examples in Table 1 were made by using the same procedureas shown in Example 3. Intermediate 1 was coupled with the appropriateamine Various coupling reagents could be used other than the onedescribed in Example 3 such as BOP, PyBop, EDC/HOBt or HATU.

TABLE 1

HPLC LCMS Method, Example R (M + H)⁺ RT (min.) ¹H NMR 4

396.1 E: 1.56 F: 1.55 (500 MHz, DMSO-d₆) δ 12.92-12.70 (m, 1H), 8.34(dd, J = 5.4, 2.1 Hz, 1H), 7.97-7.84 (m, 2H), 7.75-7.56 (m, 1H),7.56-7.47 (m, 2H), 7.47-7.34 (m, 2H), 7.25-7.05 (m, 4H), 4.77 (s, 1H),4.66 (s, 1H), 3.97-3.84 (m, 2H), 3.79 (t, J = 5.9 Hz, 1H), 3.72 (t, J =5.9 Hz, 1H), 2.79 (t, J = 5.9 Hz, 2H) 5

357.1 E: 0.95 F: 1.13 (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.69 (s, 1H),8.92 (br. s., 1H), 8.41-8.30 (m, 2H), 8.19 (d, J = 8.5 Hz, 1H),7.94-7.83 (m, 2H), 7.75- 7.66 (m, 1H), 7.60-7.55 (m, 2H), 7.55 (d, J =3.6 Hz, 1H), 7.54-7.50 (m, 2H), 3.83 (s, 2H) 6

370.1 E: 1.50 F: 1.50 (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 8.62 (t, J =5.5 Hz, 1H), 8.34 (dd, J = 6.3, 2.8 Hz, 1H), 7.95-7.83 (m, 2H),7.78-7.63 (m, 1H), 7.57-7.51 (m, J = 8.0 Hz, 2H), 7.49-7.40 (m, J = 8.0Hz, 2H), 7.36-7.29 (m, 2H), 7.29-7.22 (m, 3H), 4.31 (d, J = 6.1 Hz, 2H),3.60 (s, 2H) 7

357.1 E: 0.98 F: 1.13 (500 MHz, DMSO-d₆) δ 12.84 (s, 1H), 11.39 (s, 1H),8.65 (d, J = 6.3 Hz, 2H), 8.45-8.29 (m, 1H), 7.97 (d, J = 6.6 Hz, 2H),7.93-7.84 (m, 2H), 7.80-7.65 (m, 1H), 7.63-7.55 (m, J = 8.0 Hz, 2H),7.55-7.43 (m, J = 8.0 Hz, 2H), 3.93 (s, 2H) 8

384.1 E: 1.54 F: 1.53 (500 MHz, DMSO-d₆) δ 12.83 (br. s., 1H), 8.41-8.29(m, 1H), 7.96-7.85 (m, 2H), 7.73-7.63 (m, 1H), 7.60- 7.14 (m, 9H),4.81-4.50 (m, 2H), 3.95-3.82 (m, 2H), 3.10-2.80 (m, 3H) 9

396.2 E: 1.09 F: 1.34 ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 12.03(br. s., 1H), 8.37- 8.29 (m, 1H), 7.93-7.85 (m, 2H), 7.72-7.66 (m, 1H),7.61-7.53 (m, 4H), 7.47 (dd, J = 5.8, 3.3 Hz, 2H), 7.14 (dd, J = 5.5,3.0 Hz, 2H), 3.93 (s, 2H) 10

397.1 E: 1.29 F: 1.31 ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 8.34(dd, J = 6.2, 2.9 Hz, 1H), 7.94-7.83 (m, 2H), 7.76-7.67 (m, 1H),7.58-7.45 (m, 5H), 7.26- 7.20 (m, 1H), 7.20-7.15 (m, 1H), 3.87 (br. s.,2H) 11

424.4 C: 2.63 D: 3.80 ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H),8.34 (d, J = 6.1 Hz, 1H), 7.88 (br. s., 2H), 7.68 (d, J = 6.7 Hz, 1H),7.55 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H), 7.32-7.23 (m, 2H),7.20 (d, J = 6.7 Hz, 3H), 4.58 (d, J = 11.3 Hz, 1H), 4.13 (d, J = 12.8Hz, 1H), 3.87 (br. s., 2H), 3.13 (t, J = 13.0 Hz, 1H), 2.82-2.71 (m,1H), 2.66 (t, J = 2.4 Hz, 1H), 1.77 (t, J = 14.5 Hz, 2H), 1.51-1.34 (m,2H) 12

439.4 C: 2.41 D: 3.63 ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H),8.34 (br. s., 1H), 7.89 (d, J = 3.1 Hz, 2H), 7.69 (d, J = 6.4 Hz, 1H),7.52 (d, J = 7.3 Hz, 2H), 7.39 (d, J = 7.9 Hz, 2H), 7.35-7.19 (m, 5H),3.81 (br. s., 2H), 3.57-3.45 (m, 6H), 2.31 (br. s., 4H) 13

378.4 C: 2.13 D: 3.24 ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H),8.34 (d, J = 6.1 Hz, 1H), 7.90 (br. s., 2H), 7.70 (d, J = 6.4 Hz, 1H),7.52 (d, J = 6.1 Hz, 2H), 7.40 (d, J = 7.0 Hz, 2H), 4.08 (br. s., 1H),3.78-3.68 (m, 2H), 3.23 (br. s., 3H), 2.00-1.76 (m, 5H) 14

334.3 C: 1.94 D: 3.05 ¹H NMR (400 MHz, CD₃OD/CDCl₃ (1:1)) δ 8.43 (dt, J= 4.3, 2.4 Hz, 1H), 7.84-7.64 (m, 3H), 7.55-7.46 (m, 2H), 7.42 (d, J =8.0 Hz, 2H), 3.59 (s, 2H), 3.05 (d, J = 7.0 Hz, 2H), 0.98- 0.81 (m, 1H),0.50-0.36 (m, 2H), 0.19-0.07 (m, 2H) 15

427.4 C: 2.10 D: 3.26 ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (br. s., 1H),8.44-8.28 (m, 3H), 7.89 (d, J = 3.7 Hz, 2H), 7.69 (br. s., 1H), 7.54 (d,J = 7.3 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H), 6.70-6.62 (m, 1H), 3.89 (br.s., 2H), 3.72 (br. s., 4H), 3.65 (br. s., 2H), 3.59 (br. s., 2H) 16

455.4 C: 2.23 D: 3.47 ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (br. s., 1H),8.33 (br. s., 1H), 7.88 (br. s., 2H), 7.68 (br. s., 1H), 7.53 (d, J =7.9 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 6.95-6.85 (m, 2H), 6.82 (d, J =8.5 Hz, 2H), 3.88 (br. s., 2H), 3.68 (br. s., 4H), 3.64 (br. s., 2H),2.96 (br. s., 4H) 17

438.4 C: 2.77 D: 4.04 ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H),8.34 (br. s., 1H), 7.90 (d, J = 3.7 Hz, 2H), 7.69 (d, J = 5.8 Hz, 1H),7.52 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 7.6 Hz, 2H), 7.30-7.21 (m, 2H),7.21-7.10 (m, 3H), 4.38 (d, J = 13.1 Hz, 1H), 3.98 (d, J = 11.6 Hz, 1H),3.80 (br. s., 2H), 2.96 (t, J = 12.4 Hz, 1H), 1.75 (br. s., 1H), 1.56(br. s., 2H), 0.99 (t, J = 10.2 Hz, 2H) 18

396.4 C: 2.35 D: 3.56 ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H),8.49 (br. s., 1H), 8.34 (br. s., 1H), 7.90 (d, J = 3.7 Hz, 2H), 7.71 (d,J = 5.5 Hz, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.44 (d, J = 7.3 Hz, 2H),7.29-7.21 (m, 2H), 7.19-7.06 (m, 3H), 3.52 (br. s., 2H), 2.85 (br. s.,1H), 1.97 (br. s., 1H), 1.18 (d, J = 5.8 Hz, 2H) 19

334.3 C: 1.95 D: 3.11 ¹H NM (500 MHz, DMSO-d₆) δ 12.83 (br. s., 1H),8.40 (d, J = 6.1 Hz, 1H), 8.33 (br. s., 1H), 7.89 (d, J = 3.4 Hz, 2H),7.69 (d, J = 6.7 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.9 Hz,2H), 4.25-4.11 (m, 1H), 3.46 (s, 2H), 2.22-2.11 (m, 2H), 1.96-1.83 (m,2H), 1.70-1.55 (m, 2H) 20

356.3 C: 2.21 D: 3.36 ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (br. s., 1H),10.25 (br. s., 1H), 8.33 (br. s., 1H), 7.88 (d, J = 4.0 Hz, 2H), 7.70(br. s., 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.59-7.46 (m, 4H), 7.34- 7.25(m, 2H), 7.09-6.99 (m, 1H), 3.76 (br. s., 2H) 21

413.4 C: 1.96 D: 3.20 ¹H NMR (500 MHz, DMSO-d₆) δ 12.85 (br. s., 1H),10.65 (br. s., 1H), 9.26 (br. s., 1H), 8.58 (br. s., 1H), 8.33 (br. s.,1H), 8.02 (d, J = 8.9 Hz, 1H), 7.89 (br. s., 2H), 7.71 (br. s., 1H),7.65 (d, J = 9.5 Hz, 1H), 7.55 (br. s, 4H), 3.82 (br. s., 2H) 22

370.3 C: 2.25 D: 3.52 ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (br. s., 1H),8.33 (d, J = 6.7 Hz, 1H), 7.89 (br. s., 2H), 7.73-7.62 (m, J = 7.3 Hz,1H), 7.54 (d, J = 7.3 Hz, 1H), 7.47 (br. s., 3H), 7.39 (d, J = 7.9 Hz,4H), 7.20 (br. s., 1H), 3.51 (br. s., 2H), 3.21 (br. s., 3H) 23

382.3 C: 2.48 D: 3.67 ¹H NMR (500 MHz, DMSO-d₆) δ 12.85 (br. s., 1H),8.34 (d, J = 7.3 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.96- 7.84 (m, 2H),7.72 (d, J = 7.3 Hz, 1H), 7.59-7.51 (m, 2H), 7.47 (d, J = 7.0 Hz, 2H),7.24 (d, J = 6.4 Hz, 1H), 7.18- 7.10 (m, 1H), 7.00 (t, J = 6.6 Hz, 1H),4.26-4.17 (m, 2H), 3.96 (br. s., 2H), 3.20-3.14 (m, J = 9.2 Hz, 2H) 24

414.3 C: 2.13 D: 3.25 ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H),10.09 (br. s., 1H), 8.39-8.27 (m, 1H), 7.89 (d, J = 2.4 Hz, 2H),7.74-7.65 (m, 1H), 7.58- 7.51 (m, 2H), 7.49 (d, J = 6.7 Hz, 2H), 7.26(br. s., 1H), 6.99 (d, J = 6.4 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 4.20(d, J = 6.4 Hz, 4H), 3.70 (br. s., 2H) 25

494.3 E: 0.94 F: 1.15 ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H),8.37-8.30 (m, 1H), 7.93-7.86 (m, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.55 (d,J = 7.7 Hz, 2H), 7.47 (d, J = 7.7 Hz, 2H), 7.33-7.25 (m, 2H), 7.23 (d, J= 7.7 Hz, 1H), 4.95 (d, J = 7.4 Hz, 2H), 4.67 (d, J = 4.7 Hz, 2H), 3.87(s, 2H), 3.46 (d, J = 3.3 Hz, 2H), 2.36 (br. s., 8H), 2.17 (br. s., 3H)26

361.2 C: 2.06 D: 3.11 ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H),8.33 (br. s., 1H), 7.89 (br. s., 2H), 7.69 (br. s., 1H), 7.56 (d, J =7.3 Hz, 2H), 7.48 (d, J = 4.9 Hz, 2H), 6.12 (br. s., 1H), 3.82 (br. s.,2H), 2.17 (br. s., 3H) 27

361.2 C: 2.06 D: 3.08 ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H),11.21 (br. s., 1H), 8.33 (br. s., 1H), 7.89 (d, J = 3.1 Hz, 2H), 7.70(br. s., 1H), 7.55 (d, J = 7.3 Hz, 2H), 7.49 (d, J = 7.0 Hz, 2H), 6.62(br. s., 1H), 3.78 (br. s., 2H), 2.36 (br. s., 3H) 28

363.2 C: 2.07 D: 3.13 ¹H NMR (400 MHz, DMSO-d₆) δ 12.86 (br. s., 1H),8.36-8.30 (m, 1H), 7.93-7.86 (m, 2H), 7.73-7.69 (m, 1H), 7.58-7.53 (m,2H), 7.53-7.48 (m, 2H), 7.42 (d, J = 3.5 Hz, 1H), 7.09 (br. s., 1H),3.83 (s, 2H) 29

364.2 C: 1.84 D: 2.87 ¹H NMR (400 MHz, DMSO-d₆) δ 12.85 (s, 1H), 9.11(s, 1H), 8.37- 8.30 (m, 1H), 7.95-7.85 (m, 2H), 7.74-7.68 (m, 1H),7.59-7.53 (m, 2H), 7.53-7.48 (m, 2H), 3.92 (s, 2H) 30

392.2 C: 2.12 D: 3.18 ¹H NMR (400 MHz, DMSO-d₆) δ 12.86 (br. s., 1H),11.67 (br. s., 1H), 8.40 (d, J = 9.5 Hz, 1H), 8.36-8.30 (m, 1H),7.94-7.85 (m, 3H), 7.74- 7.66 (m, 1H), 7.60-7.55 (m, 2H), 7.55-7.49 (m,2H), 3.92 (s, 2H) 31

378.2 C: 1.81 D: 3.07 ¹H NMR (400 MHz, DMSO-d₆) δ 12.86 (s, 1H), 12.70(br. s., 1H), 8.36- 8.30 (m, 1H), 7.93-7.85 (m, 2H), 7.75-7.66 (m, 1H),7.60-7.53 (m, 2H), 7.53-7.46 (m, 2H), 3.92 (s, 2H), 2.60 (s, 3H) 32

396.1 A: 9.56 B: 9.14 (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.41-8.29 (m,1H), 7.96 (d, J = 8.3 Hz, 1H), 7.91-7.85 (m, 2H), 7.73-7.68 (m, 1H),7.62-7.52 (m, J = 8.3 Hz, 2H), 7.48-7.42 (m, J = 8.0 Hz, 2H), 7.05 (s,1H), 6.95 (d, J = 8.3 Hz, 1H), 4.21 (t, J = 8.5 Hz, 2H), 3.94 (s, 2H),3.14 (t, J = 8.4 Hz, 2H), 2.25 (s, 3H) 33

426.1 A: 9.62 B: 9.23 (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.42-8.30 (m,1H), 7.94-7.84 (m, 2H), 7.80-7.65 (m, 2H), 7.62- 7.51 (m, J = 8.0 Hz,2H), 7.51-7.40 (m, J = 8.3 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.56 (dd,J = 8.0, 2.5 Hz, 1H), 4.24 (t, J = 8.3 Hz, 2H), 4.02-3.89 (m, 4H), 3.09(t, J = 8.3 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H) 34

396.1 E: 1.70 F: 1.73 (500 MHz, DMSO-d₆) δ 12.81 (s, 1H), 8.37-8.29 (m,1H), 7.95- 7.87 (m, 2H), 7.66 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.7 Hz,3H), 7.33 (br. s., 2H), 7.19 (d, J = 6.9 Hz, 2H), 7.13 (d, J = 7.2 Hz,1H), 3.99 (s, 2H), 3.75 (t, J = 6.2 Hz, 2H), 2.66 (br. s., 2H), 1.86(quin, J = 6.5 Hz, 2H) 35

450.2 E: 1.91 F: 1.96 (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.42-8.30 (m,2H), 7.98- 7.84 (m, 2H), 7.80-7.67 (m, 1H), 7.57 (d, J = 8.0 Hz, 2H),7.48 (d, J = 8.3 Hz, 3H), 7.37 (d, J = 7.7 Hz, 1H), 4.32 (t, J = 8.5 Hz,2H), 4.01 (s, 2H), 3.29-3.24 (m, 2H) 39

410.15 E: 1.88 F: 1.89 (500 MHz, DMSO-d₆) δ 12.85 (br. s., 1H),8.38-8.32 (m, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.93-7.86 (m, 2H),7.76-7.68 (m, 1H), 7.61- 7.53 (m, J = 8.4 Hz, 2H), 7.50- 7.44 (m, J =7.9 Hz, 2H), 7.27 (d, J = 7.4 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H),7.08-7.00 (m, 1H), 3.98 (d, J = 8.9 Hz, 4H), 1.31 (s, 6H) 40

396.15 E: 1.75 F: 1.77 (500 MHz, CD₃OD) δ 8.47-8.41 (m, 1H), 8.10 (d, J= 8.4 Hz, 1H), 7.88-7.77 (m, 3H), 7.63-7.55 (m, 3H), 7.49 (d, J = 7.4Hz, 2H), 7.25-7.17 (m, 2H), 7.06 (t, J = 7.4 Hz, 1H), 4.05 (d, J = 15.4Hz, 1H), 3.95 (d, J = 15.9 Hz, 1H), 3.43 (dd, J = 15.6, 8.7 Hz, 1H),2.72 (d, J = 15.4 Hz, 1H), 1.38 (d, J = 5.9 Hz, 3H), 1.29 (br. s., 1H)41

412.0 A: 8.50 B: 7.65 (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.45-8.27 (m,1H), 7.94- 7.85 (m, 2H), 7.79-7.67 (m, 2H), 7.63-7.53 (m, J = 8.0 Hz,2H), 7.52-7.43 (m, J = 8.0 Hz, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.58 (dd,J = 8.3, 2.2 Hz, 1H), 4.25 (t, J = 8.4 Hz, 2H), 3.96 (s, 2H), 3.70 (s,3H), 3.10 (t, J = 8.4 Hz, 2H)

EXAMPLE 362-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(isoindolin-2-yl)ethanone

To a vial containing Intermediate 4 (34.8 mg, 0.091 mmol),4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol) and potassium phosphate(44 mg, 0.21 mmol), were added dioxane (0.9 mL) and water (0.1 mL). Themixture was degassed (evacuated and flushed with Ar (3×)). To thismixture was added Pd(Ph₃P)₄ (4.8 mg, 4.2 μmol). The mixture was degassed(3×), then the vial was sealed. The vial was heated in a microwavereactor at 150° C. for 25 min. The mixture was concentrated, then wasdiluted with 4 mL 1:1 DMSO/MeOH. TFA (0.1 mL) was added, then thesuspension was filtered and the solid collected. The solid was washedwith H₂O (˜5 mL), then MeOH (˜5 mL), sucked dry and dried in vacuo toafford 34.8 mg (42%) of Example 36 as a white solid.

MS (ESI) m/z: 400.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.89 (s, 1H),8.38-8.32 (m, 1H), 7.92 (quind, J=7.1, 1.7 Hz, 2H), 7.76-7.71 (m, 1H),7.51 (t, J=7.8 Hz, 1H), 7.43 (dd, J=10.5, 1.4 Hz, 1H), 7.41-7.37 (m,3H), 7.35-7.30 (m, 2H), 5.02 (s, 2H), 4.71 (s, 2H), 3.92 (s, 2H); HPLCRT=7.96 min (Method A), 8.02 min (Method B).

EXAMPLE 374-(2-fluoro-4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

To a vial containing Intermediate 5 (34.8 mg, 0.091 mmol),4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol) and potassium phosphate(44.1 mg, 0.208 mmol), were added dioxane (0.9 mL) and water (0.1 mL).The mixture was degassed (evacuated and flushed with Ar (3×)). To thismixture was added Pd(Ph₃P)₄ (4.8 mg, 4.15 μmol). The mixture wasdegassed (3×), then the vial was sealed. The vial was heated in amicrowave reactor at 150° C. for 25 min. The reaction mixture separatedinto two phases upon cooling. The organic phase was collected and waspurified by preparative HPLC to afford 11.7 mg (35%) of Example 37.

MS (ESI) m/z: 400.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.94 (br. s.,1H), 8.37-8.29 (m, 1H), 7.92-7.86 (m, 2H), 7.65-7.49 (m, 4H), 7.45-7.28(m, 4H), 4.99 (s, 2H), 4.71 (s, 2H), 3.93 (s, 2H); HPLC RT=1.56 min(Method E), 1.52 min (Method F).

EXAMPLE 384-(4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)isoquinolin-1(2H)-one

According to the procedure for the preparation of Example 36, couplingof Intermediate 6 (30 mg, 0.13 mmol) and Intermediate 9 (51 mg, 0.14mmol) afforded 17 mg (33%) of Example 38.

MS (ESI) m/z: 381.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.43 (d, J=5.8Hz, 1H), 8.29 (dd, J=8.1, 1.2 Hz, 1H), 7.69 (td, J=7.7, 1.4 Hz, 1H),7.61-7.51 (m, 2H), 7.44-7.35 (m, 6H), 7.33-7.28 (m, 2H), 7.08 (s, 1H),4.97 (s, 2H), 4.69 (s, 2H), 3.84 (s, 2H); HPLC RT=8.20 min (Method A),7.53 min (Method B).

EXAMPLE 424-(4-(1-(indolin-1-yl)-1-oxopropan-2-yl)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 3, coupling ofIntermediate 11 (13 mg, 0.044 mmol) and indoline (7.9 mg, 0.066 mmol)using HATU afforded 8.2 mg (46%) of Example 42.

MS (ESI) m/z: 396.15 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.85 (s, 1H),8.38-8.30 (m, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.92-7.84 (m, 2H), 7.74-7.68(m, 1H), 7.62-7.55 (m, J=8.4 Hz, 2H), 7.55-7.49 (m, J=8.4 Hz, 2H), 7.20(d, J=7.4 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.02-6.94 (m, 1H), 4.37 (td,J=10.4, 6.4 Hz, 1H), 4.23 (q, J=6.4 Hz, 1H), 3.91-3.75 (m, 1H),3.16-3.00 (m, 2H), 1.46 (d, J=6.4 Hz, 3H); HPLC RT=1.77 min (Method E),1.75 min (Method F).

EXAMPLE 434-(4-(1-(isoindolin-2-yl)-1-oxopropan-2-yl)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 3, coupling ofIntermediate 11 (13 mg, 0.044 mmol) and isoindoline (7.9 mg, 0.066 mmol)using HATU afforded 9.0 mg (52%) of Example 43.

MS (ESI) m/z: 396.15 (M+H)⁺; ¹H NMR (500 MHz, 1:1 CD₃OD/CDCl₃) δ8.49-8.43 (m, 1H), 7.90-7.83 (m, 2H), 7.83-7.78 (m, 1H), 7.61-7.58 (m,2H), 7.57-7.52 (m, 2H), 7.35-7.23 (m, 4H), 5.04 (d, J=13.9 Hz, 1H),4.92-4.85 (m, 1H), 4.83-4.77 (m, 1H), 4.66 (d, J=13.9 Hz, 1H), 4.09 (q,J=6.9 Hz, 1H), 1.58 (d, J=6.9 Hz, 3H).

EXAMPLE 44N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

EXAMPLE 44A N-(4-bromophenyl)-2,3-dihydro-1H-indene-2-carboxamide

To a solution of 2,3-dihydro-1H-indene-2-carboxylic acid (141 mg, 0.872mmol) in DMF (3 mL), were added 4-bromoaniline (150 mg, 0.872 mmol),PyBOP (499 mg, 0.959 mmol), and DIEA (0.457 mL, 2.62 mmol). The mixturewas stirred at rt for 16 h. The reaction mixture was concentrated andthe residue was dissolved in EtOAc, washed with 10% LiCl, 1N HCl andbrine. The crude product was purified via flash chromatography to afford90 mg (33%) of Example 44A.

MS (ESI) m/z: 316.0 (M+H)⁺.

EXAMPLE 44BN-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

A mixture of Example 44A (62 mg, 0.20 mmol), bis(pinacolato)diboron(74.7 mg, 0.294 mmol), and potassium acetate (57.7 mg, 0.588 mmol) indioxane (3 mL) was degassed (3× vacuum/Ar). PdCl₂(dppf) CH₂Cl₂ adduct(4.3 mg, 5.9 μmol) was added. The reaction mixture was degassed again(3× vacuum/Ar), sealed in a vial and heated at 110° C. for 2 h. Thereaction mixture was filtered and concentrated to afford 40 mg (56%) ofExample 44B, which was used as is in the following step.

MS (ESI) m/z: 364.2 (M+H)⁺.

EXAMPLE 44

To 4-chlorophthalazin-1(2H)-one (28.3 mg, 0.157 mmol), Example 44B (40mg, 0.11 mmol) and potassium phosphate (76 mg, 0.36 mmol), were addeddioxane (3 mL) and water (0.5 mL). The mixture was degassed (evacuatedand flushed with Ar (5×)). Pd(PPh₃)₄ (8.2 mg, 7.1 μmol) was added, thenthe mixture was degassed (2×). The reaction vial was sealed and heatedin a microwave reactor at 150° C. for 25 min. The reaction mixture wasconcentrated, then was purified by preparative HPLC to yield 17.1 mg(24%) of Example 44.

MS (ESI) m/z: 382.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.79 (s, 1H),10.26 (s, 1H), 8.38-8.31 (m, 1H), 7.93-7.85 (m, 2H), 7.84-7.79 (m, J=8.5Hz, 2H), 7.76-7.69 (m, 1H), 7.59-7.50 (m, J=8.5 Hz, 2H), 7.24 (dd,J=5.1, 3.4 Hz, 2H), 7.15 (dd, J=5.4, 3.2 Hz, 2H), 3.46 (t, J=8.5 Hz,1H), 3.21 (dd, J=8.4, 3.2 Hz, 4H); HPLC RT=1.67 min (Method E), 1.66 min(Method F).

EXAMPLE 45N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

To a mixture of Intermediate 3 (25 mg, 0.105 mmol),2-(pyridin-4-yl)thiazole-4-carboxylic acid (44 mg, 0.21 mmol), and HATU(60 mg, 0.16 mmol) in THF (1 mL), were added DIEA (0.046 mL, 0.26 mmol)and DMF (1 mL). The mixture was stirred at rt for 2 h, then wasconcentrated. The crude product was purified via preparative HPLC toafford 25 mg (36%) of Example 45.

MS (ESI) m/z: 426.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (s, 1H),10.53 (s, 1H), 8.86 (d, J=4.1 Hz, 2H), 8.73 (s, 1H), 8.44-8.32 (m, 1H),8.25 (d, J=6.1 Hz, 2H), 8.12-8.02 (m, 2H), 7.97-7.86 (m, 2H), 7.82-7.76(m, 1H), 7.68-7.60 (m, 2H); HPLC RT=5.13 min (Method A), 5.69 min(Method B).

The following examples in Table 2 were made by using the same procedureas shown in Example 45. Intermediate 3 was coupled with the appropriatecarboxylic acid. Various coupling reagents could be used other than theone described in Example 45, such as BOP, PyBop, EDC/HOBt or T3P.

TABLE 2

HPLC LCMS Method, Example R (M + H)⁺ RT (min.) ¹H NMR 46

425.1 E: 1.83 F: 1.88 (500 MHz, DMSO-d₆) δ 12.83 (br. s., 1H), 10.44(br. s., 1H), 8.58-8.51 (m, 1H), 8.35 (dd, J = 7.6, 1.2 Hz, 1H), 8.18(dd, J = 7.6, 2.1 Hz, 2H), 8.11-8.04 (m, J = 8.5 Hz, 2H), 8.00-7.86 (m,2H), 7.78 (d, J = 7.4 Hz, 1H), 7.66-7.61 (m, J = 8.5 Hz, 2H), 7.61-7.55(m, 3H) 47

426.0 E: 1.11 F: 1.52 (500 MHz, DMSO-d₆) δ 12.85 (s, 1H), 10.91 (s, 1H),8.96 (s, 1H), 8.82 (d, J = 5.8 Hz, 2H), 8.40-8.33 (m, 1H), 8.30 (d, J =5.8 Hz, 2H), 8.09-8.01 (m, J = 8.5 Hz, 2H), 7.96-7.87 (m, 2H), 7.77 (d,J = 7.4 Hz, 1H), 7.71-7.63 (m, J = 8.5 Hz, 2H) 48

493.2 E: 1.98 F: 1.99 (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.52 (s, 1H),8.64 (s, 1H), 8.41 (d, J = 8.3 Hz, 2H), 8.38-8.32 (m, 1H), 8.10-8.03 (m,J = 8.5 Hz, 2H), 7.98-7.86 (m, 4H), 7.81- 7.74 (m, 1H), 7.67-7.56 (m, J= 8.5 Hz, 2H) 49

461.2 E: 1.87 F: 1.88 1H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.51(s, 1H), 8.77- 8.68 (m, 1H), 8.63 (s, 1H), 8.35 (dd, J = 7.6, 1.2 Hz,1H), 8.13-8.02 (m, J = 8.5 Hz, 2H), 7.98-7.85 (m, 2H), 7.81-7.74 (m,1H), 7.65-7.61 (m, J = 8.5 Hz, 2H), 7.58 (ddd, J = 11.6, 9.2, 2.3 Hz,1H), 7.45-7.34 (m, 1H) 50

363.2 E: 1.46 F: 1.47 (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.91 (s, 1H),8.34 (dd, J = 7.6, 1.5 Hz, 1H), 8.10-8.00 (m, J = 8.8 Hz, 2H), 7.91 (td,J = 7.4, 1.4 Hz, 2H), 7.78-7.70 (m, 2H), 7.63- 7.53 (m, J = 8.5 Hz, 1H),2.53 (s, 3H) 51

418.2 E: 0.98 F: 1.31 (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.92 (s, 1H),8.34 (d, J = 7.2 Hz, 1H), 8.08-8.00 (m, J = 8.5 Hz, 2H), 7.96- 7.84 (m,2H), 7.74 (d, J = 7.7 Hz, 1H), 7.63-7.54 (m, J = 8.5 Hz, 2H), 3.72 (s,2H), 2.97-2.92 (m, 2H), 2.83-2.76 (m, 2H), 2.42 (s, 3H) 52

346.2 E: 1.03 F: 1.26 (500 MHz, DMSO-d₆) δ 12.81 (s, 1H), 10.55 (s, 1H),8.38-8.29 (m, 1H), 8.06- 7.98 (m, J = 8.5 Hz, 2H), 7.94-7.86 (m, 2H),7.75 (d, J = 7.4 Hz, 1H), 7.62- 7.53 (m, J = 8.5 Hz, 2H), 7.47 (s, 1H),7.11 (s, 1H), 4.02 (s, 3H) 53

403.15 E: 1.70 F: 1.71 (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.85 (s,1H), 8.34 (dd, J = 7.6, 1.2 Hz, 1H), 8.07-8.01 (m, J = 8.5 Hz, 2H),7.96-7.85 (m, 2H), 7.74 (d, J = 7.4 Hz, 1H), 7.63-7.53 (m, J = 8.5 Hz,2H), 2.87 (dt, J = 15.7, 5.8 Hz, 4H), 1.91-1.77 (m, 4H) 54

470.25 E: 1.61 F: 1.62 (500 MHz, DMSO-d₆) δ 12.78 (s, 1H), 10.05 (s,1H), 8.35-8.31 (m, 1H), 7.89 (td, J = 4.6, 1.8 Hz, 2H), 7.79-7.75 (m, J= 8.5 Hz, 2H), 7.75- 7.68 (m, 1H), 7.55-7.47 (m, J = 8.5 Hz, 2H),7.37-7.29 (m, 4H), 7.27-7.20 (m, 1H), 3.48 (s, 2H), 2.96-2.84 (m, 2H),2.41-2.29 (m, 1H), 1.98 (t, J = 11.1 Hz, 2H), 1.84- 1.75 (m, 2H),1.75-1.64 (m, 2H) 55

391.2 E: 1.06 F: 1.07 (500 MHz, DMSO-d₆) δ 12.78 (s, 1H), 10.13 (s, 1H),8.35-8.30 (m, 1H), 7.96-7.86 (m, 2H), 7.82- 7.75 (m, J = 8.5 Hz, 2H),7.72 (d, J = 8.5 Hz, 1H), 7.56-7.47 (m, J = 8.5 Hz, 2H), 4.42 (d, J =13.2 Hz, 1H), 3.89 (d, J = 12.1 Hz, 1H), 3.09 (t, J = 12.0 Hz, 1H),2.66-2.58 (m, 2H), 1.84 (t, J = 13.1 Hz, 2H), 1.69- 1.57 (m, 1H),1.53-1.39 (m, 1H) 56

439.3 E: 1.05 F: 1.15 (500 MHz, DMSO-d₆) δ 12.78 (s, 1H), 10.05 (s, 1H),8.35-8.31 (m, 1H), 7.89 (td, J = 4.6, 1.8 Hz, 2H), 7.79-7.75 (m, J = 8.5Hz, 2H), 7.75- 7.68 (m, 1H), 7.55-7.47 (m, J = 8.5 Hz, 2H), 7.37-7.29(m, 4H), 7.27-7.20 (m, 1H), 3.48 (s, 2H), 2.96-2.84 (m, 2H), 2.41-2.29(m, 1H), 1.98 (t, J = 11.1 Hz, 2H), 1.84- 1.75 (m, 2H), 1.75-1.64 (m,2H) 57

393.2 E: 1.01 F: 0.99 (500 MHz, DMSO-d₆) δ 10.14 (br. s., 1H), 8.33 (d,J = 7.4 Hz, 1H), 7.94-7.86 (m, 2H), 7.80-7.74 (m, J = 8.3 Hz, 2H), 7.72(d, J = 7.2 Hz, 1H), 7.57-7.46 (m, J = 8.3 Hz, 2H), 3.45 (t, J = 5.5 Hz,3H), 3.26 (s, 3H), 3.12-3.03 (m, 1H), 2.96 (br. s., 1H), 2.73 (br. s.,1H), 2.63 (br. s., 3H), 2.01 (d, J = 6.9 Hz, 2H) 58

385.3 E: 1.38 F: 1.59 (500 MHz, DMSO-d₆) δ 12.80 (s, 1H), 10.07 (s, 1H),8.34 (d, J = 8.0 Hz, 1H), 7.97-7.86 (m, 6H), 7.76 (d, J = 7.7 Hz, 1H),7.55 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 3.01 (s, 6H) 59

425.25 E: 1.16 F: 1.26 (500 MHz, DMSO-d₆) δ 12.79 (s, 1H), 10.11 (br.s., 1H), 8.39-8.29 (m, 1H), 7.93-7.86 (m, 2H), 7.79- 7.73 (m, J = 8.5Hz, 2H), 7.72-7.67 (m, 1H), 7.54-7.48 (m, J = 8.5 Hz, 2H), 7.40-7.31 (m,4H), 7.28 (br. s., 1H), 3.67 (br. s., 2H), 3.14 (br. s., 1H), 2.96 (br.s., 1H), 2.82-2.69 (m, 2H), 2.59 (br. s., 1H), 2.07 (br. s., 2H) 60

411.2 E: 1.76 F: 1.74 (500 MHz, DMSO-d₆) δ 12.80 (s, 1H), 10.03 (s, 1H),8.34 (d, J = 7.7 Hz, 1H), 7.97 (s, 2H), 7.93-7.86 (m, 4H), 7.77 (d, J =7.7 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 6.62 (d, J = 8.5 Hz, 2H), 1.99(br. s., 4H) 61

425.25 E: 1.23 F: 1.83 (500 MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.34 (d, J =7.7 Hz, 1H), 7.99- 7.86 (m, 6H), 7.76 (d, J = 7.4 Hz, 1H), 7.56 (d, J =8.3 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.34 (br. s., 4H), 1.60 (br. s.,6H) 62

411.2 E: 1.55 F: 1.80 ¹H NMR (500 MHz, DMSO-d₆) δ 12.81 (s, 1H), 10.31(s, 1H), 8.38- 8.32 (m, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.94-7.85 (m,2H), 7.76 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.36- 7.27 (m,1H), 7.19 (d, J = 7.4 Hz, 1H), 7.07 (s, 1H), 6.75 (dd, J = 8.0, 1.7 Hz,1H), 3.31 (br. s., 4H), 1.99 (t, J = 6.2 Hz, 4H) 63

427.25 E: 1.42 F: 1.46 (500 MHz, DMSO-d₆) δ 12.81 (br. s., 1H), 10.18(s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.06-7.86 (m, 6H), 7.80-7.73 (m, 1H),7.56 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 3.82-3.71 (m, 4H),3.29-3.22 (m, 4H) 64

440.25 E: 1.06 F: 1.18 ¹H NMR (500 MHz, DMSO-d₆) δ 12.80 (s, 1H), 10.14(s, 1H), 8.34 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.94-7.86(m, 4H), 7.76 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.04 (d, J= 8.3 Hz, 2H), 2.46 (br. s., 4H), 2.23 (s, 3H) 65

408.2 E: 1.05 F: 1.29 ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.55(s, 1H), 8.38 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 8.00-7.86(m, 7H), 7.76 (d, J = 7.7 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.62 (d, J= 8.5 Hz, 2H), 7.17 (s, 1H) 66

385.1 E: 1.16 F: 1.64 (500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H), 10.35 (s,1H), 8.40-8.31 (m, 1H), 8.00-7.86 (m, 4H), 7.76 (d, J = 7.4 Hz, 1H),7.59 (d, J = 8.4 Hz, 2H), 7.38-7.32 (m, 1H), 7.28-7.23 (m, 2H), 6.95(dd, J = 8.2, 2.2 Hz, 1H), 2.98 (s, 6H) 67

342.2 E: 1.47 F: 1.47 (500 MHz, DMSO-d₆) δ 12.84 (s, 1H), 10.48 (s, 1H),8.35 (dd, J = 7.7, 1.2 Hz, 1H), 8.04-7.96 (m, 4H), 7.95-7.88 (m, 2H),7.80-7.73 (m, 1H), 7.65-7.52 (m, 5H)

EXAMPLE 68 4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenylisoindoline-2-carboxylate

EXAMPLE 68A 4-bromophenyl isoindoline-2-carboxylate

To a solution of isoindoline (167 mg, 1.401 mmol) and DIEA (0.445 mL,2.55 mmol) in CH₂Cl₂ (3 mL), was added 4-bromophenyl carbonochloridate(300 mg, 1.274 mmol). The mixture was stirred at rt for 1h, then wasquenched with water. The mixture was diluted with EtOAc (100 mL), thenwas washed with 1N HCl, sat Na₂CO₃ and brine, dried over Na₂SO₄, andconcentrated. The crude product was purified via flash chromatography toafford 310 mg (76%) of Example 68A.

MS (ESI) m/z: 318.0 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.53-7.48 (m, 2H),7.36-7.29 (m, 4H), 7.13-7.07 (m, 2H), 4.94 (s, 2H), 4.84 (s, 2H)

EXAMPLE 68B (4-((isoindoline-2-carbonyl)oxy)phenyl)boronic acid

A mixture of Example 68A (100 mg, 0.314 mmol), bis(pinacolato)diboron(104 mg, 0.409 mmol), and potassium acetate (93 mg, 0.943 mmol) indioxane (3 mL) was degassed (3× vacuum/Ar). PdCl₂(dppf) CH₂Cl₂ adduct(6.90 mg, 9.43 μmol) was added, then the reaction mixture was degassedagain (3× vacuum/Ar), sealed in a vial and heated at 110° C. for 2 h.The reaction was concentrated and purified via preparative HPLC toafford 75 mg (84%) of Example 68B.

MS (ESI) m/z: 284.1 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.83-7.76 (m, 1H),7.68 (d, J=8.1 Hz, 1H), 7.40-7.28 (m, 4H), 7.24-7.10 (m, 2H), 4.95 (s,2H), 4.78 (s, 2H).

EXAMPLE 68

To 4-chlorophthalazin-1(2H)-one (18.24 mg, 0.101 mmol), Example 68B (26mg, 0.092 mmol) and potassium phosphate (48.7 mg, 0.230 mmol), wereadded dioxane (3 mL) and water (0.5 mL). The mixture was degassed(evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (5.31 mg, 4.59 μmol) wasadded, then the mixture was degassed (2×). The reaction vial was sealedand heated in a microwave reactor at 150° C. for 25 min. The crudeproduct was purified by preparative HPLC to afford 9 mg (20%) of Example68.

MS (ESI) m/z: 384.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (s, 1H),8.45-8.29 (m, 1H), 7.92 (qd, J=7.3, 5.8 Hz, 2H), 7.75-7.69 (m, 1H),7.67-7.59 (m, 2H), 7.46-7.37 (m, 4H), 7.36-7.28 (m, 2H), 4.96 (s, 2H),4.76 (s, 2H); HPLC RT=1.77 min (Method E), 1.78 min (Method F).

EXAMPLE 69 4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl3-phenylpyrrolidine-1-carboxylate

EXAMPLE 69A 4-bromophenyl 3-phenylpyrrolidine-1-carboxylate

To a mixture of 3-phenylpyrrolidine (141 mg, 0.956 mmol) and DIEA (0.223mL, 1.274 mmol) in CH₂Cl₂ (3 mL) at 0° C., was added 4-bromophenylcarbonochloridate (150 mg, 0.637 mmol). The mixture was stirred at rtfor 1h. The reaction mixture was quenched with water and EtOAc (100 mL)was added. The organic phase was washed with 1N HCl, sat Na₂CO₃ andbrine, dried over Na₂SO₄, concentrated and purified flash chromatographyto afford 210 mg (95%) of Example 69A.

MS (ESI) m/z: 345.9 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.56-7.44 (m, 2H),7.40-7.34 (m, 2H), 7.31-7.26 (m, 3H), 7.09-6.99 (m, 2H), 4.12-3.94 (m,1H), 3.89-3.73 (m, 1H), 3.64 (td, J=10.2, 6.7 Hz, 1H), 3.60-3.40 (m,3H), 2.36 (ddtd, J=18.5, 12.4, 6.3, 2.6 Hz, 1H), 2.18-2.01 (m, 1H).

EXAMPLE 69B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl3-phenylpyrrolidine-1-carboxylate

To a mixture of Example 69A (210 mg, 0.607 mmol), bis(pinacolato)diboron(185 mg, 0.728 mmol), and potassium acetate (179 mg, 1.820 mmol) indioxane (5 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (13.31 mg, 0.018mmol). The reaction mixture was degassed (3× vacuum/Ar), sealed in avial and heated at 110° C. for 2 h. The reaction mixture was dilutedwith water and extracted with EtOAc. The organic phase was concentrated,then purified via flash chromatography (EtOAc/hexanes) to afford 220 mg(92%) of Example 69B.

MS (ESI) m/z: 394.2 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.86 (dd, J=7.8,3.7 Hz, 2H), 7.42-7.35 (m, 2H), 7.33-7.26 (m, 3H), 7.22 (t, J=7.0 Hz,2H), 4.13-3.99 (m, 1H), 3.92-3.77 (m, 1H), 3.72-3.41 (m, 3H), 2.38 (t,J=13.1 Hz, 1H), 2.19-2.07 (m, 1H), 1.37 (s, 12H).

EXAMPLE 69

To 4-chlorophthalazin-1(2H)-one (28 mg, 0.16 mmol), Example 69B (79 mg,0.20 mmol) and potassium phosphate (82 mg, 0.39 mmol), were addeddioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuatedand flushed with Ar (5×)). Pd(PPh₃)₄ (9.0 mg, 7.8 μmol) was added, thenthe mixture was degassed (2×). The reaction vial was sealed and heatedin a microwave reactor at 150° C. for 35 min. The reaction mixture wasconcentrated, then was purified by preparative HPLC to afford 8.2 mg(10%) of the Example 69.

MS (ESI) m/z: 412.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.85 (s, 1H),8.35 (d, J=7.4 Hz, 1H), 7.99-7.86 (m, 2H), 7.70 (d, J=7.4 Hz, 1H), 7.62(dd, J=8.5, 3.9 Hz, 2H), 7.44-7.30 (m, 6H), 7.29-7.19 (m, 1H), 4.13-3.97(m, 1H), 3.97-3.76 (m, 1H), 3.72-3.59 (m, 1H), 3.55-3.42 (m, 2H),2.42-2.26 (m, 1H), 2.17-1.99 (m, 1H); HPLC RT=1.73 min (Method E), 1.74min (Method F).

EXAMPLE 70 4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl5-methoxyisoindoline-2-carboxylate

EXAMPLE 70A 4-bromophenyl 5-methoxyisoindoline-2-carboxylate

To a solution of 5-methoxyisoindoline (80 mg, 0.54 mmol) and DIEA (0.18mL, 1.02 mmol) in CH₂Cl₂ (3 mL) at 0° C., was added 4-bromophenylcarbonochloridate (120 mg, 0.51 mmol). The reaction mixture was stirredrt for 1h, then was quenched with water. The mixture was diluted withEtOAc (100 mL). The organic phase was washed with 1N HCl, sat. Na₂CO₃and brine, dried over Na₂SO₄, and concentrated. The crude product waspurified via flash chromatography to afford 112 mg (63%) of Example 70A.

MS (ESI) m/z: 348.0 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.55-7.45 (m, 2H),7.19 (dd, J=12.2, 8.4 Hz, 1H), 7.13-7.03 (m, 2H), 6.88 (dd, J=8.4, 2.3Hz, 1H), 6.82 (dd, J=10.5, 1.9 Hz, 1H), 4.87 (d, J=16.2 Hz, 2H), 4.78(d, J=17.1 Hz, 2H), 3.83 (s, 3H).

EXAMPLE 70B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl5-methoxyisoindoline-2-carboxylate

To a mixture of Example 70A (112 mg, 0.322 mmol), bis(pinacolato)diboron(98 mg, 0.39 mmol), and potassium acetate (95 mg, 0.97 mmol) in dioxane(10 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (7.1 mg, 9.7 μmol). Thereaction mixture was degassed (3× vacuum/Ar), sealed in a vial andheated at 110° C. for 2 h. The reaction was diluted with water andextracted with EtOAc. The organic phase was concentrated and the residuewas purified via flash chromatography to afford 100 mg (79%) of Example70B.

MS (ESI) m/z: 396.2 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.85 (d, J=8.3 Hz,2H), 7.25-7.15 (m, 3H), 6.92-6.80 (m, 2H), 4.89 (d, J=16.5 Hz, 2H), 4.79(d, J=18.2 Hz, 2H), 3.83 (s, 3H), 1.44-1.32 (m, 12H).

EXAMPLE 70

To 4-chlorophthalazin-1(2H)-one (13 mg, 0.072 mmol), Example 70B (29.9mg, 0.076 mmol) and potassium phosphate (38.2 mg, 0.180 mmol), wereadded dioxane (3 mL) and water (0.33 mL). The mixture was degassed(evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (4.2 mg, 3.6 μmol) wasadded, then the mixture was degassed (2×). The reaction vial was sealedand heated in a microwave reactor at 150° C. for 25 min. The reactionmixture was concentrated, then was purified via preparative HPLC toafford 9 mg (23%) of Example 70.

MS (ESI) m/z: 414.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (s, 1H),8.35 (dd, J=7.6, 1.2 Hz, 1H), 7.98-7.88 (m, 2H), 7.76-7.70 (m, 1H),7.68-7.61 (m, J=8.5 Hz, 2H), 7.43-7.36 (m, J=8.5 Hz, 2H), 7.30 (d, J=8.3Hz, 1H), 6.99 (br. s., 1H), 6.91 (d, J=8.3 Hz, 1H), 4.92 (s, 1H), 4.87(s, 1H), 4.72 (s, 1H), 4.68 (s, 1H), 3.81-3.72 (m, 3H); HPLC RT=9.48 min(Method A), 8.98 min (Method B).

EXAMPLE 71 4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl5-fluoroisoindoline-2-carboxylate

EXAMPLE 71A 4-bromophenyl 5-fluoroisoindoline-2-carboxylate

To a mixture of 5-fluoroisoindoline (141 mg, 1.03 mmol) and DIEA (0.326mL, 1.87 mmol) in CH₂Cl₂ (3 mL) at 0° C., was added 4-bromophenylcarbonochloridate (220 mg, 0.934 mmol). The mixture was stirred at rtfor 1h, then was quenched with water. The mixture was diluted with EtOAc(100 mL), then was washed with 1N HCl, sat Na₂CO₃ and brine, dried overNa₂SO₄, and concentrated. The crude product was purified via flashchromatography (EtOAc/hexanes) to afford 190 mg (61%) of Example 71A.

MS (ESI) m/z: 414.1 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.56-7.46 (m, 2H),7.34-7.21 (m, 1H), 7.16-7.07 (m, 2H), 7.05-6.97 (m, 2H), 4.92 (d, J=14.0Hz, 2H), 4.82 (d, J=14.0 Hz, 2H).

EXAMPLE 71B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl5-fluoroisoindoline-2-carboxylate

To a mixture of Example 71A (182 mg, 0.541 mmol), bis(pinacolato)diboron(165 mg, 0.65 mmol), and potassium acetate (159 mg, 1.62 mmol) indioxane (4 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (11.9 mg, 0.016mmol). The reaction mixture was degassed (3× vacuum/Ar), sealed in avial and heated at 110° C. for 2 h. The reaction mixture was partitionedbetween EtOAc and H₂O. The organic phase was concentrated and theresidue was purified via flash chromatography to afford 150 mg (72%) ofExample 71B.

MS (ESI) m/z: 384.2 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.88-7.83 (m, 2H),7.28-7.19 (m, 3H), 7.09-6.95 (m, 2H), 4.93 (d, J=14.3 Hz, 2H), 4.82 (d,J=14.0 Hz, 2H), 1.43-1.34 (m, 12H).

EXAMPLE 71

To 4-chlorophthalazin-1(2H)-one (20 mg, 0.11 mmol), Example 71B (44.6mg, 0.116 mmol) and potassium phosphate (58.8 mg, 0.277 mmol), wereadded dioxane (3 mL) and water (0.33 mL). The mixture was degassed(evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (6.4 mg, 5.5 μmol) wasadded, then the mixture was degassed (2×). The reaction vial was sealedand heated in a microwave reactor at 150° C. for 25 min. The reactionmixture was concentrated and the residue purified via preparative HPLCto afford 5 mg (8%) of Example 71.

MS (ESI) m/z: 402.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (s, 1H),8.39-8.32 (m, 1H), 7.95-7.89 (m, 2H), 7.75-7.69 (m, 1H), 7.66-7.60 (m,2H), 7.44-7.35 (m, 4H), 7.29-7.15 (m, 4H), 4.94 (d, J=17.3 Hz, 2H), 4.74(d, J=17.1 Hz, 2H); HPLC RT=9.62 min (Method A), 9.15 min (Method B).

EXAMPLE 72 4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate, 2 TFA

EXAMPLE 72A 4-bromophenyl5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate, 2 TFA

To a solution of Intermediate 2 (196 mg, 0.849 mmol) and DIEA (0.297 mL,1.70 mmol) in CH₂Cl₂ (3 mL) at 0° C., was added 4-bromophenylcarbonochloridate (200 mg, 0.849 mmol). The mixture was stirred at rtfor 1h. The reaction mixture was quenched with water and diluted withEtOAc (100 mL). The organic phase was washed with 1N HCl, sat Na₂CO₃ andbrine, dried over Na₂SO₄ and concentrated. The crude product waspurified by flash chromatography, followed by preparative HPLC to afford280 mg (50%) of Example 72A.

MS (ESI) m/z: 430.1 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD) δ 7.60-7.51 (m, 2H),7.49-7.38 (m, 3H), 7.21-7.10 (m, 2H), 4.96 (s, 2H), 4.79 (s, 2H), 4.15(s, 2H), 3.49 (br. s., 4H), 3.30-3.19 (m, 4H), 2.94 (s, 3H).

EXAMPLE 72B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate

To a mixture of Example 72A (70 mg, 0.106 mmol), bis(pinacolato)diboron(32.4 mg, 0.128 mmol), and potassium acetate (31.3 mg, 0.319 mmol) indioxane (10 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (2.3 mg, 3.2 μmol).The reaction mixture was degassed (3× vacuum/Ar), sealed in a vial andheated at 110° C. for 2 h. The reaction was quenched with water, thenextracted with EtOAc. The organic phase was concentrated to afford 80 mgof Example 72B, which was used as is in the following step withoutfurther purification.

MS (ESI) m/z: 478.4 (M+H)⁺

EXAMPLE 72

To a vial containing 4-chlorophthalazin-1(2H)-one (22 mg, 0.12 mmol),Example 72B (80 mg, 0.106 mmol) and potassium phosphate (64.6 mg, 0.305mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture wasdegassed (evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (7.0 mg, 6.1μmol) was added, then the mixture was degassed (2×). The reaction vialwas sealed and heated in a microwave reactor at 150° C. for 25 min. Thereaction mixture was concentrated and purified via preparative HPLC toafford 22 mg (25%) of Example 72.

MS (ESI) m/z: 496.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (s, 1H),8.43-8.31 (m, 1H), 8.02-7.86 (m, 2H), 7.71 (d, J=7.7 Hz, 1H), 7.65 (d,J=8.8 Hz, 2H), 7.47-7.34 (m, 4H), 7.30 (d, J=7.4 Hz, 1H), 4.95 (s, 2H),4.76 (br. s., 2H), 3.65 (br. s., 2H), 2.99 (br. s., 4H), 2.77 (br. s.,3H), 2.36 (br. s., 2H); HPLC RT=4.32 min (Method A), 5.17 min (MethodB).

EXAMPLE 73 4-(4-((5-phenyloxazol-2-yl)amino)phenyl)phthalazin-1(2H)-one

EXAMPLE 73A N-(4-bromophenyl)-5-phenyloxazol-2-amine

To a solution of 2-azido-1-phenylethanone (Angew. Chem. Int. Ed. 2007,46, 4489-4491) (126 mg, 0.782 mmol) and 1-bromo-4-isothiocyanatobenzene(167 mg, 0.782 mmol) in dioxane (4 mL) at 80° C., was addedtriphenylphosphine (205 mg, 0.782 mmol). The mixture was stirred at 85°C. for 30 min, then was cooled to rt. The reaction mixture wasconcentrated. The solid was recrystallized from hot CH₃Cl (˜5 mL). Theprecipitate was suspended in EtOAc (˜3 mL), filtered and collected toafford 134 mg (54%) of Example 73A as a white solid.

MS (ESI) m/z: 315.0 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.62-7.57 (m, 2H),7.51-7.46 (m, 2H), 7.46-7.41 (m, 2H), 7.39 (t, J=7.7 Hz, 2H), 7.26 (dt,J=7.4, 1.3 Hz, 1H), 7.24 (s, 1H).

EXAMPLE 73B5-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazol-2-amine

To a vial containing Example 73A (136 mg, 0.432 mmol),bis(pinacolato)diboron (164 mg, 0.647 mmol) and potassium acetate (127mg, 1.30 mmol), was added dioxane (2 mL). The mixture was degassed(evacuated and flushed with Ar (3×)). PdCl₂(dppf)-CH₂Cl₂ adduct (17.6mg, 0.022 mmol) was added, then the mixture was degassed (2×), then wassealed. The mixture was stirred at 110° C. for 2 h. The reaction mixturewas diluted with EtOAc. The organic phase was washed with H₂O and brine,dried (Na₂SO₄) and concentrated. The crude product was purified by flashchromatography (gradient from 0 to 50% ethyl acetate/hexanes) to afford122 mg (78%) of Example 73B as a white solid.

MS (ESI) m/z: 363.1 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J=8.8 Hz,2H), 7.55 (dd, J=8.3, 1.2 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.43 (s, 1H),7.42-7.36 (m, 2H), 7.29-7.23 (m, 1H), 7.18 (s, 1H), 1.35 (s, 12H)

EXAMPLE 73

To 4-chlorophthalazin-1(2H)-one (36.7 mg, 0.203 mmol), Example 73B (67mg, 0.185 mmol) and potassium phosphate (98 mg, 0.46 mmol) in dioxane (3mL) and water (0.5 mL), was added Pd(PPh₃)₄ (10.7 mg, 9.25 μmol). Themixture was degassed (3×), then the reaction vial was sealed and heatedin a microwave reactor at 150° C. for 25 min. The crude product waspurified by preparative HPLC to afford 9.7 mg (11%) of Example 73.

MS (ESI) m/z: 381.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.78 (s, 1H),10.60 (s, 1H), 8.40-8.30 (m, 1H), 7.96-7.87 (m, 2H), 7.84-7.73 (m, 3H),7.62 (d, J=7.7 Hz, 2H), 7.57 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 7.45 (t,J=7.7 Hz, 2H), 7.33-7.24 (m, 1H); HPLC RT=8.99 min (Method A), 8.46 min(Method B).

EXAMPLE 74 4-(4-((4-phenylthiazol-2-yl)amino)phenyl)phthalazin-1(2H)-one

EXAMPLE 74A N-(4-bromophenyl)-4-phenylthiazol-2-amine

2-bromo-1-phenylethanone (105 mg, 0.528 mmol) and1-(4-bromophenyl)thiourea (122 mg, 0.528 mmol) were mixed in glycerol (5mL) and stirred at 90° C. for 2 h. The reaction mixture was partitionedbetween EtOAc and water. The organic phase was concentrated and purifiedvia flash chromatography (EtOAc/hexanes) to afford 165 mg (94%) ofExample 74A.

MS (ESI) m/z: 331.0 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.87-7.82 (m, 2H),7.44-7.38 (m, 4H), 7.36-7.31 (m, 1H), 7.29-7.22 (m, 2H), 6.84 (s, 1H)

EXAMPLE 74B4-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-amine

To a mixture of Example 74A (160 mg, 0.483 mmol), bis(pinacolato)diboron(147 mg, 0.580 mmol), and potassium acetate (142 mg, 1.45 mmol) indioxane (10 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (10.6 mg, 0.014mmol). The reaction mixture was degassed (3× vacuum/Ar), sealed in avial and heated at 110° C. for 2 h. The reaction was diluted with waterand extracted with EtOAc. The organic phase was concentrated and theproduct purified via flash chromatography to afford 130 mg (71%) ofExample 74B.

MS (ESI) m/z: 379.0 (M+H)⁺.

EXAMPLE 74

To 4-chlorophthalazin-1(2H)-one (18 mg, 0.10 mmol), Example 74B (45.2mg, 0.120 mmol) and potassium phosphate (53 mg, 0.25 mmol), were addeddioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuatedand flushed with Ar (5×)). Pd(PPh₃)₄ (5.8 mg, 5.0 μmol) was added, thenthe mixture was degassed (2×). The reaction vial was sealed and heatedin a microwave reactor at 150° C. for 35 min. The reaction mixture wasconcentrated, then was purified by preparative HPLC to afford 2.0 mg(3.9%) of Example 74.

MS (ESI) m/z: 397.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.78 (s, 1H),10.53 (s, 1H), 8.39-8.31 (m, 1H), 8.01-7.86 (m, 6H), 7.81 (d, J=7.4 Hz,1H), 7.59 (d, J=8.5 Hz, 2H), 7.48-7.38 (m, 3H), 7.37-7.30 (m, 1H); HPLCRT=1.85 min (Method E), 1.90 min (Method F).

EXAMPLE 75 4-(4-(benzo[d]oxazol-2-ylamino)phenyl)phthalazin-1(2H)-one

Intermediate 3 (35 mg, 0.100 mmol), 2-chlorobenzo[d]oxazole (0.015 mL,0.130 mmol), and DIEA (0.087 mL, 0.498 mmol) were dissolved in NMP (1mL) and the reaction mixture was heated in a capped vial at 150° C. for18 h. The reaction mixture was purified by preparative HPLC to afford5.0 mg (14%) of Example 75.

MS (ESI) m/z: 355.05 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H),10.90 (br. s., 1H), 8.39-8.30 (m, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.93-7.87(m, 2H), 7.80-7.76 (m, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.51 (dd, J=16.6,7.7 Hz, 2H), 7.28-7.22 (m, 1H), 7.19-7.14 (m, 1H); HPLC RT=1.58 min(Method E), 1.64 min (Method F).

EXAMPLE 76N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)indoline-1-carboxamide

To 4-chlorophthalazin-1(2H)-one (29 mg, 0.16 mmol), Intermediate 10 andpotassium phosphate (85 mg, 0.40 mmol), were added dioxane (3 mL) andwater (0.33 mL). The mixture was degassed (evacuated and flushed with Ar(5×)). Pd(PPh₃)₄ (9.28 mg, 8.03 μmol) was added, then the mixture wasdegassed (2×). The reaction vial was sealed and heated in a microwavereactor at 150° C. for 30 min. The reaction mixture was concentrated andpurified via preparative HPLC to afford 6.1 mg (9.4%) of Example 76.

MS (ESI) m/z: 383.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.81 (s, 1H),8.74 (s, 1H), 8.34 (dd, J=7.7, 1.2 Hz, 1H), 8.00-7.85 (m, 3H), 7.76 (d,J=8.9 Hz, 3H), 7.53 (d, J=8.4 Hz, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.14 (t,J=7.7 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 4.18 (t, J=8.7 Hz, 2H), 3.20 (t,J=8.7 Hz, 2H); HPLC RT=1.65 min (Method E), 1.66 min (Method F).

EXAMPLE 77N-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)indoline-1-carboxamide

According to the procedure for the preparation of Example 76, couplingof Intermediate 6 (28 mg, 0.125 mmol) and Intermediate 10 (54.6 mg,0.150 mmol) afforded 7.5 mg (16%) of Example 77.

MS (ESI) m/z: 382.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.41 (br. s.,1H), 8.63 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H),7.75-7.66 (m, 3H), 7.59-7.51 (m, 2H), 7.35 (d, J=8.3 Hz, 2H), 7.21 (d,J=7.4 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 7.07 (s, 1H), 6.91 (t, J=7.3 Hz,1H), 4.17 (t, J=8.5 Hz, 2H), 3.20 (t, J=8.3 Hz, 2H); HPLC RT=1.77 min(Method E), 1.73 min (Method F).

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: M is N; L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and—NR⁶—; R¹ is selected from OC₁₋₄ alkyl, NR⁵R⁵, C₃₋₁₀ carbocycle and 4-to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycle,and heterocycle are substituted with 1-4 R⁷; R², at each occurrence, isindependently selected from halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, CN, —NH₂,—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H, —CH₂CO₂H, —CO₂(C₁₋₄ alkyl),—CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,—OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄ alkyl),—SO₂NH₂, —C(═NH)NH₂, carbocycle, and heterocycle, wherein said alkyl,alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; R³, at each occurrence, is independentlyselected from halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄haloalkyl, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, —CO₂H, —CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl),—CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H,—NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂,—C(═NH)NH₂, carbocycle, and heterocycle, wherein said alkyl, alkoxy,alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with0-4 R⁹; R⁴, at each occurrence, is independently selected from H,halogen, OH, NH₂, CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), C₁₋₄ alkyl, carbocycle, and heterocycle, whereinsaid alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and—(CR⁶R⁶)_(n)-4-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR⁸, O, and S(O)_(p), wherein said alkyl,carbocycle and heterocycle are substituted with 1-4 R⁷; alternatively,R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷;R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,—CH₂CONH₂, —(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹; R⁸, at each occurrence, is independently selected from H, C₁₋₄alkyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵,C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl,SO₂carbocycle, SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; alternatively, R⁸ and R⁸ are taken togetherwith the nitrogen atom to which they are attached to form a 4- to10-membered heterocycle substituted with 0-4 R⁹; R⁹, at each occurrence,is independently selected from halogen, OH, NO₂, CHF₂, CF₃, C₁₋₄ alkyl,C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b); R¹⁰ is selected from H and C₁₋₄ alkyl; R^(a), at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, —(CH₂)_(n)OH,CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b); R^(b), at each occurrence, isindependently selected from ═O, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃,NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-N(C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl),—R^(c), COR^(c), CO₂R^(c), and CONHR^(c); R^(c), at each occurrence, isindependently selected from —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to 6-membered heterocyclecontaining carbon atoms and 1-4 heteroatoms selected from the groupconsisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); wherein each ringmoiety is substituted with 0-2 R^(d); R^(d), at each occurrence, isindependently selected from ═O, halo, —OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and —NHCO(C₁₋₄ alkyl), andheterocycle containing carbon atoms and 1-4 heteroatoms selected fromthe group consisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); n, ateach occurrence, is independently selected from 0, 1, 2, 3, and 4; p, ateach occurrence, is independently selected from 0, 1, and 2; provided(1) when L is NH, R¹ is other than


2. The compound of claim 1, wherein: L is selected from —CR⁴R⁴C(O)—,—OC(O)—, and —NR⁶—; R⁴, at each occurrence, is independently selectedfrom H and C₁₋₄ alkyl; and R⁷, at each occurrence, is independentlyselected from H, ═O, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃,—(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸,—NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH,—NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p) wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹.
 3. The compoundof claim 2, having Formula (II):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: M is N; R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and—(CR⁶R⁶)_(n)-4-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR⁸, O, and S(O)_(p), wherein said alkyl,carbocycle, and heterocycle are substituted with 1-4 R⁷; alternatively,R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷;R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹; R⁸, at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, C(O)C₁₋₄alkyl,C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; R⁹, at each occurrence, is independentlyselected from halogen, OH, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy,CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b); R¹⁰ is selected from H and C₁₋₄ alkyl; R^(a), at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, —(CH₂)_(n)OH,CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b); R^(b), at each occurrence, isindependently selected from ═O, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃,NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-N(C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl),—R^(c), COR^(c), CO₂R^(c), and CONHR^(c); R^(c), at each occurrence, isindependently selected from —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to 6-membered heterocyclecontaining carbon atoms and 1-4 heteroatoms selected from the groupconsisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); wherein each ringmoiety is substituted with 0-2 R^(d); R^(d), at each occurrence, isindependently selected from ═O, halo, —OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and —NHCO(C₁₋₄ alkyl), andheterocycle containing carbon atoms and 1-4 heteroatoms selected fromthe group consisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); n, ateach occurrence, is independently selected from 0, 1, 2, 3, and 4; andp, at each occurrence, is independently selected from 0, 1, and
 2. 4.The compound of claim 3, wherein: R⁵ is selected from H, C₁₋₄ alkyl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-aryl, or —(CH₂)_(n)-4-10 memberedheterocycle selected from


5. The compound of claim 3, wherein: R⁵ and R⁵ are taken together withthe nitrogen atom to which they are attached to form a heterocycleselected from


6. The compound of claim 2, having Formula (III):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: M is N; R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and—(CR⁶R⁶)_(n)-4-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR⁸, O, and S(O)_(p), wherein said alkyl,carbocycle, and heterocycle are substituted with 1-4 R⁷; alternatively,R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷;R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹; R⁸, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C(O)C₁₋₄alkyl,C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; R⁹, at each occurrence, is independentlyselected from halogen, OH, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy,CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b); n, at each occurrence, is independently selected from 0,1, 2, 3, and 4; and p, at each occurrence, is independently selectedfrom 0, 1, and
 2. 7. The compound of claim 2, wherein: L is —NR⁶—; R¹ isselected from C₃₋₁₀ carbocycle and 5- to 10-membered heterocyclesubstituted with 1-4 R⁷; R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and—(CR⁶R⁶)_(n)-4-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR⁸, O, and S(O)_(p), wherein said alkyl,carbocycle, and heterocycle are substituted with 1-4 R⁷; alternatively,R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷;R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹; R⁸, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C(O)C₁₋₄alkyl,C(O)carbocycle, C(O)heterocycle, C(O)NR⁵R⁵, C(O)O-alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR⁵R⁵, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; R⁹, at each occurrence, is independentlyselected from halogen, OH, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy,CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)₍₂₋₄₎NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b); n, at each occurrence, is independently selected from 0,1, 2, 3, and 4; and p, at each occurrence, is independently selectedfrom 0, 1, and
 2. 8. The compound of claim 7, wherein: L is —NR⁶—; andR¹ is selected from


9. The compound of claim 1, selected from

or a stereoisomer, a tautomer or a pharmaceutically acceptable saltthereof.
 10. A pharmaceutical composition comprising one or morecompounds according to claim 1 and a pharmaceutically acceptable carrieror diluent.